Methods for treating flaviviruses and zika infections

ABSTRACT

There are provided, inter alia, methods of treatment of Zika virus infection.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 62/447,290 filed Jan. 17, 2017, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Human infection with ZIKA virus (ZIKV), a mosquito-borne flavivirus, has spread rapidly since the 2015 outbreak in Brazil, and the World Health Organization declared ZIKV infection an International Public Health Emergency in 2016. ZIKV was discovered in 1947 and, although it had previously caused only sporadic disease in Africa and Asia, more recent outbreaks occurred in Micronesia in 2007 and in French Polynesia in 2013. ZIKV infection has been identified as the etiological agent of severe neurological defects, including microcephaly during fetal development and neuronal injury associated with Guillain-Barré syndrome in adults. New modes of viral transmission, including maternal-fetal and sexual transmission have been reported. ZIKV can infect human skin explants, peripheral blood mononuclear cells, human neuroprogenitor cells, and human cerebral organoids. In mouse models, ZIKV may be neurotropic.

ZIKV and other members of the Flaviviridae family, such as dengue (DENV), West Nile (WNV), yellow fever (YFV), and Japanese encephalopathy (JEV), are positive (+) single-stranded RNA viruses. The ZIKV genome encodes a single polyprotein precursor that is cleaved by viral and host proteases to produce three structural and seven nonstructural proteins. Although our understanding of the molecular mechanisms involved in ZIKV infection of human cells has increased dramatically in the past few years, key determinants of ZIKV pathogenicity, such as cell-type specificity, mode of entry, and host factors essential for replication, are still largely unknown. In particular, there is a large gap in our understanding of the genetic and epigenetic regulatory mechanisms governing the viral life cycle and viral interactions with host cells.

Solutions to this and other problems in the art are provided. Specifically, we discovered a number of FDA approved drugs that can be used to treat ZIKV infections and possibly other flaviviruses including Dengue, West Nile, JEV, and HCV. Specifically, we performed cell-based screens using libraries of compounds containing antiviral drugs and other available potential antiviral like compounds. We have accordingly identified FDA approved drugs that inhibit ZIKV in vitro and in vivo. These drugs are well tolerated in many cell lines including stem cells and mice and potently inhibit ZIKV infection.

BRIEF SUMMARY OF THE INVENTION

In a first aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a compound as set forth in any of FIG. 1A, 1B, 2, 3, 6, 8, or 9.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of an NS5 polymerase inhibitor.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of an HIV protease inhibitor.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a calcium channel blocker.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof a combined effective amount of a therapeutic composition including an NS5 polymerase inhibitor and a HIV protease inhibitor.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a protein or a gene encoding the protein. In embodiments, the protein is a ZIKV non-structural (NS) protein. In embodiments, the ZIKV non-structural protein is NS5. In embodiments, the protein is NS5 RNA polymerase. In embodiment, the ZIKV non-structural protein is NS2B-NS3. In embodiments, the protein is NS2B-NS3 protease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B. FIG. 1A: Antiviral activity of approved drugs/clinical molecules library was tested against Zika virus in human 293 T cells at the MOI of 5. Cells were pretreated with drugs (10 μM) for 1 hour and infected with ZIKV (MOI=5). After 24 hours of infection, mRNA was isolated and the levels of cellular ZIKV was determined by qRT-PCR. FIG. 1B: Methyl transferase inhibitors potently reduced ZIKV replication. Methods were as described in FIG. 1A.

FIGS. 2A-2D. Dose dependent inhibition of Zika virus in 293 T cells by selected antiviral molecules (at the MOI of 5 using different concentration of drugs, ICso was calculated). FIG. 2A—Lopinavir. FIG. 2B—Daclatasvir. FIG. 2C—Oxyclozanide. FIG. 2D—Rafoxanide.

FIGS. 3A-3B. Synergistic activity of lopinavir and ritonavir. 293 T cells were pretreated with indicated drugs and after 1 hour, the cells were infected with ZIKV at the MOI of 5. After 24 hours, proteins were analyzed by western blotting (FIG. 3A) and mRNA was isolated and the levels of cellular ZIKV was determined by qRT-PCR (FIG. 3B).

FIG. 4. Experimental outline to determine the drug efficacy for ZIKV inhibition in vivo.

FIGS. 5A-5D. Protease inhibitors reduced ZIKV in animals (brain—FIG. 5A; blood—FIG. 5B; testes—FIG. 5C; spleen—FIG. 5D) both as prophylaxis and therapeutic regimens.

FIG. 6. Screening of additional compounds for ZIKA levels using Vero cells (in 10 μM concentration). Methods of screening were as described herein. Viral RNA released was analyzed by qRT-PCR for ZIKA. Compounds (left to right): control, berberine, fluoxetine, formoterol, genistine, U0126, dibucaine, pirlindole, suramin, mycophenolic acid, polyhydroxyalkanoates, (PHA) and niclosamide.

FIG. 7. Screening of additional compounds for ZIKA levels using Vero cells (in 10 μM concentration) as described for FIG. 6. Compounds (left to right): clomiphene, amphotericin B, and toremifene.

FIG. 8. Screening of additional compounds for ZIKA levels using Vero cells (in 10 μM concentration) as described for FIG. 6. Compounds providing hits: ganciclovir, procaine hydrochloride, zidovudine, aciclovir, drostanolone propionate, dapivirine (TMC120), tilorone hydrochloride (2,7-bis[2-(diethylamino)ethoxy]-9H-fluoren-9-one, HCl), and Docosanol.

FIGS. 9A-9K. ZIKA inhibition by various drugs in 293 cells at 20 μM, visualized by immune staining. Drugs: mock (FIG. 9A), DMSO (FIG. 9B), PHA-690509 (FIG. 9C), formoterol (FIG. 9D), fluoxetine (FIG. 9E), genistein (FIG. 9F), U0126 (FIG. 9G), berberine (FIG. 9H), dibucaine (FIG. 9I), pirlindole (FIG. 9J), and suramin (FIG. 9K). Left panels: DAPI; right panels: ZIKV.

FIGS. 10A-10E. Variable ZIKV Infection and Replication Levels in Different Cell Types. Immunohistochemistry of ZIKV gene expression in microglial (FIG. 10A), fibroblast (BJ) (FIG. 10B), kidney (293FT) (FIG. 10C), and macrophage (THP-1) (FIG. 10D) cell lines at 24 h post-infection. Cells were stained with anti-flavivirus envelope protein (ZIKVE), and nuclei were visualized with Hoechst 33258. FIG. 10E: ZIKV replication assessed by one-step RT-qPCR analysis of viral supernatants at the indicated times post-infection. Data are presented as the mean±SEM of n=3. *p<0.05, **p<0.01, ***p<0.001; ns, not significant by two-way ANOVA.

FIGS. 11A-11E. Circos plots of transcriptional changes in microglia (FIG. 11A), BJ (FIG. 11B), 293FT (FIG. 11C), and THP-1 derived macrophages (FIG. 11D) cells at 24 h post-infection. The outer circles represent the expression levels of the transcripts before infection. The inner circles represent the differentially expressed genes, with the size of the lines indicating the fold change in expression. Genes upregulated and downregulated by ZIKV infection are shown, respectively. (FIG. 11E) Circos plot showing differentially expressed genes in all four cell types. The number of differentially expressed genes and the magnitude of the expression change are inversely correlated with ZIKV expression. Upregulated genes are in red and downregulated genes are in blue. Outer to inner circles: THP-1, 293FT, BJ, and microglia.

FIG. 12A-12E. Cell Type-Specific Differences in Steady-State Expression of Viral Response Genes Reveal Potential Antiviral Targets. (FIG. 12A) Hierarchical clustering of genes associated with “response to virus” in microglia, BJ, 293FT, and THP-1 derived macrophages before infection (top) and the fold change in expression of the same genes at 24 h post-ZIKV infection (bottom). Left scale bar: 0:10 represents gene expression log 2(RPKM+1) for all cell times. Right scale bar: −2:2 represents fold change in gene expressed between mock treated and ZIKV infected cells. Also see Table 1. (FIG. 12B) Pre-infection expression levels of genes associated with “response to virus,” showing high expression in THP-1 derived macrophages compared with microglia, BJ, and 293T cells. (FIG. 12C) Hierarchical clustering of genes associated with “cell surface” (top) and their associated fold change in expression following ZIKV infection (bottom). (FIG. 12D) Differential gene expression of cell surface proteins and receptors involved in cell activation, immune response, and cell surface signaling in THP-1 derived macrophages. (FIG. 12E) Gene ontology analysis of cell surface genes highly expressed specifically in THP-1 and lowly expressed in other cell lines.

FIGS. 13A-13G. Analysis of Differentially Expressed Genes Post-ZIKV Infection Identifies Key Pathways Exploited by ZIKV. (FIG. 13A) Hierarchical clustering of differentially expressed genes following ZIKV infection, showing cell type-specific transcriptional changes. Genes displayed have fold changes of >1.4 and p<0.05 in at least one cell type. The vertical bar to the right indicates the differentially expressed gene clusters described by color in the text. (FIG. 13B) Interactome of differentially expressed genes across all cell types. (FIG. 13C) Gene ontology analysis of “red cluster” genes (vertical bar in A), which are mostly upregulated in microglia and THP-1 derived macrophages and downregulated in 293FT and BJ cells. (FIG. 13D) Gene ontology analysis of “yellow cluster” genes, which are mostly downregulated in microglia and THP-1 derived macrophages and upregulated in 293FT and BJ cells. (FIG. 13E) Analysis of “green cluster” genes, which are upregulated only in THP-1, showing enrichment in genes that modulate the adaptive immune response and complement cascades. (FIG. 13F) Analysis of “magenta cluster” genes, which are upregulated in 293FT and THP-1 derived macrophages and downregulated in microglia and BJ cells, showing enrichment in genes that regulate viral receptor activity, endothelial cells, and angiogenesis. (FIG. 13G) Analysis of “blue cluster” genes, which are upregulated in microglia cells and downregulated in BJ, 293T, and THP-1 derived macrophages, showing enrichment in genes that regulate cellular and metabolic processes.

FIGS. 14A-14D. Nucleoside Metabolic Inhibitors Attenuate ZIKV Replication. (FIG. 14A) ZIKV replication assessed by RT-qPCR analysis 48 hours post-infection in mock, ZIKV only, ZIKV plus 1 μM floxuridine or ZIKV plus 10 μM floxuridine treated microglia. Data are presented as the mean±SEM of n=3. *p<0.05, **p<0.01 by t-test. (FIG. 14B) Immunohistochemistry of ZIKV gene expression in mock, ZIKV only, ZIKV plus 1 μM floxuridine (FUDX1) or ZIKV plus 10 μM floxuridine (FUDX10) treated microglia. Cells were stained with anti-flavivirus envelope protein (ZIKVE), and nuclei were visualized with Hoechst 33258. (FIG. 14C) ZIKV replication assessed by RT-qPCR analysis 48 hours post-infection in mock, ZIKV only, ZIKV plus fluorouracil or ZIKV plus 10 μM fluorouracil treated microglia. Data are presented as the mean±SEM of n=3. *p<0.05, **p<0.01 by t-test. (FIG. 14D) Immunohistochemistry of ZIKV gene expression in mock, ZIKV only, ZIKV plus 1 μM fluorouracil (FU1) or ZIKV plus 10 μM fluorouracil (FU10) treated microglia. Cells were stained with anti-flavivirus envelope protein (ZIKVE), and nuclei were visualized with Hoechst 33258.

FIGS. 15A-15E. Amplification of MR766 ZIKV in Vero and BHK Cells (related to FIGS. 10A-10E). (FIG. 15A). Immunohistochemical staining for ZIKV expression in Vero and BHK cells. (FIG. 15B) RT-qPCR analysis of Vero, BHK, microglia, BJ, 293T, and THP-1 cell supernatants. (FIG. 15C-15E) RT-qPCR analysis of innate immune response genes TLR3, IRF3, APOBEC in microglia, BJ and THP-1 derived macrophages, respectively.

FIGS. 16A-16F. Analysis of Viral Response and Immune-Related Genes Reveals Potential Antiviral Targets (related to FIGS. 12A-12E). (FIG. 16A) Heat map of genes highly expressed in microglia, BJ, and 293T cells, but not in THP-1 derived macrophages, from the analysis of “response to virus”-associated genes in FIG. 12A. Left scale bar: 0:10 represents gene expression log 2(RPKM+1) for all cell times. Right scale bar: −2:2 represents fold change in gene expressed between mock treated and ZIKV infected cells. (FIG. 16B-16D) Hierarchical clustering of differentially expressed genes related to “modulation by virus of host gene expression” (FIG. 16B), “viral transcription” (FIG. 16C), and “viral release from host cell” (FIG. 16D) between mock-infected cells (left) and their associated fold change in expression after ZIKV infection (right). (FIG. 16E) Scatterplot of immune response genes showing higher expression of immune-related genes in THP-1 derived macrophages compared with microglia cells. (FIG. 16F) Hierarchical clustering of differentially expressed genes related to “immune response” in mock-infected cells (top) and their associated fold change in expression after ZIKV infection (bottom). Also see Table 3.

FIGS. 17A-17D. Gene ontology analysis of differentially expressed genes in microglia (FIG. 17A), BJ (FIG. 17B), 293FT (FIG. 17C), and THP-1 (FIG. 17D) cells (related to FIGS. 13A-13G).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Alkyl is not cyclized. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds (e.g. alkene, alkyne). Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., selected from the group consisting of O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroalkyl is not cyclized. The heteroatom(s) (e.g., O, N, P, S, and Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or three heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Cycloalkyl and heterocycloalkyl are non-aromatic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroarylene.

A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, monophosphate (or derivatives thereof), diphosphate (or derivatives thereof), triphosphate (or derivatives thereof), in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R, R′, R″, R′″, and R″″ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, monophosphate (or derivatives thereof), diphosphate (or derivatives thereof), triphosphate (or derivatives thereof), in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R′″, and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ groups when more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In embodiments, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—, —CRR′—, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independently integers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

A “substituent group,” as used herein, means a group selected from the following moieties:

(A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, monophosphate (or derivatives thereof), diphosphate (or derivatives thereof), or triphosphate (or derivatives thereof), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, monophosphate (or derivatives thereof), diphosphate (or derivatives thereof), or triphosphate (or derivatives thereof), substituted with at least one substituent selected from:

-   -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,         —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)         NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,         —NHSO₂CH₃, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,         unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,         unsubstituted aryl, unsubstituted heteroaryl, monophosphate (or         derivatives thereof), diphosphate (or derivatives thereof), or         triphosphate (or derivatives thereof), and     -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,         heteroaryl, monophosphate (or derivatives thereof), diphosphate         (or derivatives thereof), or triphosphate (or derivatives         thereof), substituted with at least one substituent selected         from:         -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,             —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,             —NHC(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,             —OCHF₂, —NHSO₂CH₃, —N₃, unsubstituted alkyl, unsubstituted             heteroalkyl, unsubstituted cycloalkyl, unsubstituted             heterocycloalkyl, unsubstituted aryl, unsubstituted             heteroaryl, monophosphate (or derivatives thereof),             diphosphate (or derivatives thereof), or triphosphate (or             derivatives thereof), and         -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,             heteroaryl, monophosphate (or derivatives thereof),             diphosphate (or derivatives thereof), or triphosphate (or             derivatives thereof), substituted with at least one             substituent selected from: oxo, halogen, —CF₃, —CN, —OH,             —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,             —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O) NH₂, —NHSO₂H,             —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃,             unsubstituted alkyl, unsubstituted heteroalkyl,             unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,             unsubstituted aryl, unsubstituted heteroaryl, monophosphate             (or derivatives thereof), diphosphate (or derivatives             thereof), and triphosphate (or derivatives thereof).

A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

In embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in embodiments each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In embodiments, the compound is a chemical species set forth herein.

Certain complexes and compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C₁-C₂₀ alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus, a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³ substituents are present, each R¹³ substituent may be distinguished as R^(13A), R^(13B), R^(13C), etc., wherein each of R^(13A), R^(13B), R^(13C), R^(13D), etc. is defined within the scope of the definition of R¹³ and optionally differently.

Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

“Analog,” or “analogue” are used in accordance with plain ordinary meaning within Chemistry and Biology and refer to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analogue is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

The term “pharmaceutically acceptable salts” is meant to include salts of active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

Thus, the compounds disclosed herein may exist as salts, such as with pharmaceutically acceptable acids. The compounds disclosed herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

In addition to salt forms, there are provided compounds which are in a prodrug form. Prodrugs of the compounds described herein include those compounds that readily undergo chemical or enzymatic changes under physiological conditions to provide the compounds disclosed herein. Additionally, prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds disclosed herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope disclosed herein. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses disclosed herein and are intended to be within the scope of the compounds and methods disclosed herein.

As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods disclosed herein. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

The terms “treating”, or “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.

An “effective amount” is an amount sufficient to accomplish a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the methods disclosed herein should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

“Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

“Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. Contacting may include allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.

The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A “fusion protein” refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

As defined herein, the terms “activation”, “activate”, “activating” and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g. increasing) the activity or function of the relative to the activity or function of the protein in the absence of the activator (e.g. composition described herein). Thus, in embodiments, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. The amount of activation may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more in comparison to a control in the absence of the agonist. In embodiments, the activation is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more than the expression or activity in the absence of the agonist.

As defined herein, the terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor (e.g. antagonist) interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. Thus, in embodiments, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. The amount of inhibition may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or less in comparison to a control in the absence of the antagonist. In embodiments, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more than the expression or activity in the absence of the antagonist.

As defined herein, the terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

As defined herein, the term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.

As defined herein, the term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.

As defined herein, “selective” or “selectivity” or the like of a compound refers to the compound's ability to discriminate between molecular targets. “Specific”, “specifically”, “specificity”, or the like of a compound refers to the compound's ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.

As defined herein, “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions disclosed herein without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds disclosed herein. One of skill in the art will recognize that other pharmaceutical excipients are useful in the compositions and methods disclosed herein.

As defined herein, the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

The compositions disclosed herein can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions disclosed herein may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions disclosed herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions disclosed herein into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions can also be delivered as nanoparticles.

As defined herein, the terms “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose.

As used herein, an “effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease (e.g., targeted by Zika virus, Dengue virus, West Nile virus, etc.), reduce receptor signalling activity, reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease (e.g., targeted by Zika virus, Dengue virus, West Nile virus, etc.)), which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). An “effective amount” refers to an antiviral drug or a composition of an antiviral drug in an amount that is sufficient to reduce the amount and/or kill virus (Zika virus, Dengue virus, West Nile virus, etc.). The virus is contacted with an amount of the antiviral drug or composition thereof (an NS5 polymerase inhibitor or HIV protease inhibitor, or combinations thereof) effective to reduce and/or kill virus. When used herein in reference to administration to a subject in need thereof, the terms “amount effective” or “effective amount” mean an amount of an NS5 polymerase inhibitor or HIV protease inhibitor, or combinations thereof which treat a viral infection. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period which the individual dosage unit is to be used, the bioavailability of the composition, the route of administration, etc. It is understood, however, that specific amounts of an NS5 polymerase inhibitor or HIV protease inhibitor, or combinations thereof for any particular subject depends upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the composition combination, severity of the particular cancer being treated and form of administration.

In certain embodiments, the NS5 polymerase inhibitor and HIV protease inhibitor are administered in a combined synergistic amount. A “combined synergistic amount” as used herein refers to the sum of a first amount (e.g., an amount of an NS5 polymerase inhibitor) and a second amount (e.g., an amount of an HIV protease inhibitor) that results in a synergistic effect (i.e. an effect greater than an additive effect). Therefore, the terms “synergy”, “synergism”, “synergistic”, “combined synergistic amount”, and “synergistic therapeutic effect” which are used herein interchangeably, refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds administered alone as a single agent.

In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the NS5 polymerase inhibitor when used separately from the HIV protease inhibitor. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the HIV protease inhibitor when used separately from the NS5 polymerase inhibitor.

The synergistic effect may be a disease-treating effect such as a disease triggered by Zika virus, Dengue virus, West Nile virus, etc.

The NS5 polymerase inhibitor and the HIV protease inhibitor may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines or separate tablets) or sequentially (e.g., one agent is administered first followed by administration of the second agent). Thus, the term combination is used to refer to concomitant, simultaneous or sequential administration of the NS5 polymerase inhibitor and the HIV protease inhibitor.

In embodiments, the NS5 polymerase inhibitor and the HIV protease inhibitor are administered simultaneously or sequentially. In embodiments, the NS5 polymerase inhibitor and the HIV protease inhibitor are administered simultaneously. In embodiments, the NS5 polymerase inhibitor and the HIV protease inhibitor are administered sequentially. During the course of treatment the NS5 polymerase inhibitor and the HIV protease inhibitor may at times be administered sequentially and at other times be administered simultaneously.

Pharmaceutical compositions may include compositions wherein the active ingredient (e.g., compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms.

The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

The compounds described herein can be used in combination with one another, with other active drugs known to be useful in treating a disease or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. Thus, the compounds described herein may be co-administered with one another or with other active drugs known to be useful in treating a disease.

By “co-administer” it is meant that a compound described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds described herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances.

Co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Also contemplated herein, are embodiments, where co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. The active and/or adjunctive agents may be linked or conjugated to one another.

The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g., toxicity) is caused by (in whole or in part) the substance or substance activity or function.

“Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

“Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In embodiments, the disease or condition is ZIKA infection.

The term “ZIKA infection,” “Zika fever” or the like refer, in the usual and customary sense, to a viral infection due to the Zika virus (ZIKV), a member of the Flaviviridae family. The Zika virus is typically enveloped and icosahedral, having a nonsegmented, single-stranded, 10 kilobase positive-sense RNA genome.

The term “nucleic acid” refers to deoxyribonucleotides (DNA) or ribonucleotides (RNA) and polymers thereof in either single- or double-stranded form, and complements thereof. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).

The term “antibody” refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Typically, the antigen-binding region of an antibody will be most critical in specificity and affinity of binding. In some embodiments, antibodies or fragments of antibodies may be derived from different organisms, including humans, mice, rats, hamsters, camels, etc. Antibodies of the invention may include antibodies that have been modified or mutated at one or more amino acid positions to improve or modulate a desired function of the antibody (e.g. glycosylation, expression, antigen recognition, effector functions, antigen binding, specificity, etc.).

An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.

For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. Nos. 4,946,778, 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio/Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Pat. No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).

Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U.S. Pat. Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87/02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239:1534). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81:6851-6855 (1984), Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3):169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.

An “antisense nucleic acid” as referred to herein is a nucleic acid (e.g. DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid (e.g. an mRNA translatable into a protein) and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA) or reducing the translation of the target nucleic acid (e.g. mRNA) or altering transcript splicing (e.g. single stranded morpholino oligo). See, e.g., Weintraub, Scientific American, 262:40 (1990). Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) are generally between 15 and 25 bases in length. Thus, antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid (e.g. target mRNA). In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid sequence (e.g. mRNA) under stringent hybridization conditions. In embodiments, the antisense nucleic acid hybridizes to the target nucleic acid (e.g. mRNA) under moderately stringent hybridization conditions. Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides. Antisense nucleic acids include, for example, siRNA, mircoRNA and the like.

A “siRNA,” “small interfering RNA,” “small RNA,” or “RNAi” as provided herein, refers to a nucleic acid that forms a double stranded RNA, which double stranded RNA has the ability to reduce or inhibit expression of a gene or target gene when present in the same cell as the gene or target gene. The complementary portions of the nucleic acid that hybridize to form the double stranded molecule typically have substantial or complete identity. In one embodiment, a siRNA or RNAi is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA. In embodiments, the siRNA inhibits gene expression by interacting with a complementary cellular mRNA thereby interfering with the expression of the complementary mRNA. Typically, the nucleic acid is at least about 15-50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15-50 nucleotides in length, and the double stranded siRNA is about 15-50 base pairs in length). In other embodiments, the length is 20-30 base nucleotides, preferably about 20-25 or about 24-29 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

As used herein, “viral (ZIKA) non-structural (NS) protein” refers to a protein encoded by virus (e.g., ZIKA virus) that is an RNA-binding protein that plays an integral role in virus replication.

As used herein, “ZIKV non-structural protein 5 (NS5)” refers to an RNA-dependent RNA polymerase that plays an essential role in viral replication in the infected host cytoplasm and contributes integrally to pathogenesis by localizing in the host cell nucleus. NS5 is comprised of two domains. The N-terminal domain binds GTP and can perform two biochemically distinct methylation reactions required for RNA cap formation. The C-terminal domain contains RNA-dependent RNA polymerase activity. ZIKV NS5 is recognized with high affinity by the host cell importin α/β1 heterodimer, thus representing a validated target for compounds capable of blocking that interaction.

As used herein, “ZIKV NS5 polymerase inhibitors” refer to compounds capable of preventing viral replication by selectively binding to NS5 polymerase and blocking its interaction with the host cell importin α/β1 heterodimer. The compounds shown to exhibit an inhibitory activity against ZIKA NS5 polymerase include, but are not limited to, beclabuvir, dasabuvir, deleobuvir, filibuvir, setrobuvir, radalbuvir, sofosbuvir, N-(4-hydroxyphenyl) retinamide (4-HPR), 2,1-benzothiazine-2,2-dioxide, or chloroquine (Q).

As used herein, “ZIKV non-structural protein NS2B-NS3 (NS2B-NS3)” is an HIV protease, which consists of the NS2B cofactor and the NS3 protease domain, both of which are essential for cleavage of the ZIKV polyprotein precursor and generation of fully functional viral proteins.

As used herein, “ZIKV NS2B-NS3 HIV protease inhibitors” refer to compounds capable of preventing viral replication by selectively binding to NS2B-NS3 HIV protease and blocking proteolytic cleavage of protein precursors that are necessary for production of infectious viral particles. The compounds shown to exhibit an inhibitory activity against ZIKA NS2B-NS3 HIV protease include, but are not limited to, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.

As used herein, “calcium channel” refers to an ion channel which shows selective permeability to calcium ions. Voltage-gated or voltage-dependent calcium channels (VDCCs) is a group of voltage-gated ion channels found in the membranes of excitable (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion. Activation of particular VDCCs allows calcium ions to rush into the cell, which, depending on the cell type, results in activation of calcium-sensitive potassium channels, muscular contraction, excitation of neurons, up-regulation of gene expression, or release of hormones or neurotransmitters. Ligand-gated ion channels (LICs, LGIC), also commonly referred as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na⁺, K⁺, Ca²⁺, and/or Cl⁻ to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

As used herein, “calcium channel blockers” (CCB) refer to compounds that are capable of disrupting the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris. Calcium channel blockers can be in short-acting and long-acting forms. Short-acting calcium channel blockers work quickly, but their effects lasts for a few hours. Long-acting medications are slowly released to provide a longer lasting effect. Available calcium channel blockers include, but are not limited to, Amlodipine, Aranidipine, Azelnidipine, Barnidipine Benidipine, Clevidipine, Efonidipine, Felodipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Pranidipine, Diltiazem, and Verapamil.

Methods

In a first aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a compound as set forth in any of FIG. 1A1B, 2A-2D, 3A-3B, 6, 8, or 9A-9K.

In embodiments, the compound is Ganciclovir, Procaine hydrochloride, Zidovudine, Acyclovir, Drostanolone Propionate, Dapivirine (TMC120), Tilorone hydrochloride, Docosanol, Suramin, Clomiphene, Amphotericin B, Toremifene, Mycophenolic acid, Fluoxetine, Niclosamide, or polyhydroxyalkanoate (PHA). In the embodiments below, the compounds are identified by their IUPAC chemical names.

In embodiments, the compound is Ganciclovir (also referred to herein as 9-(1,3-dihydroxy-2-propoxymethyl)guanine), CAS Number 824 10-32-0.

In embodiments, the compound is Procaine hydrochloride (also referred to herein as 4-amino-, 2-(diethylamino) ethyl ester monohydrochloride), CAS Number: 51-05-8.

In embodiments, the compound is Zidovudine (also referred to herein as 3′-deoxy-3′-azido-thymidine or 1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione), CAS Number 30516-87-1.

In embodiments, the compound is Acyclovir (also referred to herein as 2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-3H-purin-6-one), CAS Number 59277-89-3.

In embodiments, the compound is Drostanolone Propionate (also referred to herein as (2R,5S,8R,9S,10S,13S,14S,17S)-17-hydroxy-2,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one), CAS Number 58-19-5.

In embodiments, the compound is Dapivirine (also referred to herein as 4-{[4-(mesitylamino)-2-pyrimidinyl]amino}benzonitrile, CAS Number 244767-67-7.

In embodiments, the compound is Tilorone hydrochloride (also referred to herein as 2,7-Bis(2-diethylaminoethoxy)fluoren-9-one hydrochloride); CAS Number 27591-69-1.

In embodiments, the compound is Docosanol having CAS number 661-19-8.

In embodiments, the compound is Suramin (also referred to herein as 8,8′-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid), CAS Number 145-63-1.

In embodiments, the compound is Clomiphene (also referred to herein as (E,Z)-2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-N,N-diethylethanamine), CAS Number 911-45-5.

In embodiments, the compound is Amphotericin B (also referred to herein as (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,21E,23E,25E,27E,29E,31E,33R,35S,36R,37S)-33-[(3-amino-3,6-dideoxy-β-D-mannopyranosyl)oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo [33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid); CAS Number 1397-89-3.

In embodiments, the compound is Toremifene (also referred to herein as 2-[4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy]-N,N-dimethylethanamine), CAS number 89778-26-7.

In embodiments, the compound is Mycophenolic acid (also referred to herein as (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid), CAS Number 24280-93-1.

In embodiments, the compound is Fluoxetine (also referred to herein as N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine), CAS Number 54910-89-3.

In embodiments, the compound is Niclosamide (also referred to herein as 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide), CAS Number 50-65-7.

In embodiments, the compound is polyhydroxyalkanoate (PHA).

In another aspect, there is provided a method of treating a Zika viral infection. The method comprises administering to a subject in need thereof an effective amount of an NS5 polymerase inhibitor.

In embodiments, the NS5 polymerase inhibitor is beclabuvir, dasabuvir, deleobuvir, filibuvir, setrobuvir, radalbuvir, or sofosbuvir.

In embodiments, the NS5 polymerase inhibitor is beclabuvir (also referred to herein as (1aR,12bS)-8-Cyclohexyl-N-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide), CAS Number 958002-33-0.

In embodiments, the NS5 polymerase inhibitor is dasabuvir (also referred to herein as N-{6-[5-(2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-methoxy-3-(2-methyl-2-propanyl)phenyl]-2-naphthyl}methanesulfonamide), CAS Number 1132935-63-7.

In embodiments, the NS5 polymerase inhibitor is deleobuvir (also referred to herein as (2E)-3-(2-{1-[2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl 1-1-methyl-1H-benzimidazol-6-yl)prop-2-enoic acid), CAS Number 863884-77-9.

In embodiments, the NS5 polymerase inhibitor is filibuvir (also referred to herein as (2R)-2-cyclopentyl-2-[2-(2,6-diethylpyridin-4-yl)ethyl]-5-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-3H-pyran-6-one), CAS Number 877130-28-4.

In embodiments, the NS5 polymerase inhibitor is setrobuvir (also referred to herein as N-(3-1(4aR,5S,8R,8aS)-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-octahydro-5,8-methanoquinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ⁶,2,4-benzothiadiazin-7-yl)methanesulfonamide), CAS Number 1071517-39-9.

In embodiments, the NS5 polymerase inhibitor is radalbuvir (also referred to herein as 5-(3,3-Dimethylbut-1-yn-1-yl)-3-{(1R)—N-[(1s,4s)-4-hydroxy-4-(1[(3S)-oxolan-3-yl]oxy}methyl)cyclohexyl]-4-methylcyclohex-3-ene-1-carboxamido}thiophene-2-carboxylic acid), CAS Number 1314795-11-3.

In embodiments, the NS5 polymerase inhibitor is sofosbuvir (also referred to herein as Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate), CAS Number 1190307-88-0.

In another aspect, there is provided a method of treating a Zika viral infection. The method comprises administering to a subject in need thereof an effective amount of an HIV protease inhibitor.

In embodiments, the HIV protease inhibitor is amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.

In embodiments, the HIV protease inhibitor is amprenavir (also referred to herein as (3S)-oxolan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate), CAS Number 161814-49-9.

In embodiments, the HIV protease inhibitor is atazanavir (also referred to herein as methyl N-[(1S)-1-{[(2S,3S)-3-hydroxy-4-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-N′-1-[4-(pyridin-2-yl)phenyl]methyl}butanehydrazido]-1-phenylbutan-2-yl]carbamoyl}-2,2-dimethylpropyl]carbamate), CAS Number 198904-31-3.

In embodiments, the HIV protease inhibitor is darunavir (also referred to herein as [(1R,5S,6R)-2,8-dioxabicyclo[3.3.0]oct-6-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl-butan-2-yl]carbamate), CAS Number 206361-99-1.

In embodiments, the HIV protease inhibitor is fosamprenavir (also referred to herein as [(1R,3S)-1-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-3-(1[(3S)-oxolan-3-yloxy]carbonyl}amino)-4-phenylbutan-2-yl]oxy}phosphonic acid), CAS Number 226700-81-8.

In embodiments, the HIV protease inhibitor is indinavir (also referred to herein as (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4-1[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}butyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide), CAS Number 150378-17-9.

In embodiments, the HIV protease inhibitor is lopinavir (also referred to herein as (2S)—N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide), CAS Number 192725-17-0.

In embodiments, the HIV protease inhibitor is nelfinavir (also referred to herein as (3S,4aS,8aS)—N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), CAS Number 159989-64-7.

In embodiments, the HIV protease inhibitor is ritonavir (also referred to herein as 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate), CAS Number 155213-67-5.

In embodiments, the HIV protease inhibitor is saquinavir (also referred to herein as (2S)—N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide), CAS Number 127779-20-8.

In embodiments, the HIV protease inhibitor is tipranavir (also referred to herein as N-{3-[(1R)-1-[(2R)-6-hydroxy-4-oxo-2-(2-phenylethyl)-2-propyl-3,4-dihydro-2H-pyran-5-yl]propyl]phenyl}-5-(trifluoromethyl)pyridine-2-sulfonamide), CAS Number 17-44-84-41-4.

In embodiments, the HIV protease inhibitor is asunaprevir (also referred to herein as 3-Methyl-N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-valyl-(4R)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-vinylcyclopropyl}-L-prolinamide), CAS Number 630420-16-5.

In embodiments, the HIV protease inhibitor is boceprevir (also referred to herein as (1R,5S)—N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide), CAS Number 394730-60-0.

In embodiments, the HIV protease inhibitor is grazoprevir (also referred to herein as (1R,18R,20R,24S,27S)—N-1(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-vinylcyclopropyl}-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.03,12.05,10.0 18,20]nonacosa-3,5,7,9,11-pentaene-27-carboxamide), CAS Number 1350514-68-9.

In embodiments, the HIV protease inhibitor is paritaprevir (also referred to herein as (2R,6S,12Z,13 aS,14aR,16aS)—N-(Cyclopropylsulfonyl)-6-1[(5-methyl-2-pyrazinyl)carbonyl]amino}-5,16-dioxo-2-(6-phenanthridinyloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide), CAS Number 1216941-48-8.

In embodiments, the HIV protease inhibitor is simeprevir (also referred to herein as (2R,3aR,10Z,11aS,12aR,14aR)—N-(Cyclopropylsulfonyl)-2-{[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy}-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide), CAS Number 923604-59-5.

In embodiments, the HIV protease inhibitor is telaprevir (also referred to herein as (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide), CAS Number 402957-28-2.

In another aspect, there is provided a method of treating a Zika viral infection. The method comprises administering to a subject in need thereof an effective amount of a protein or a gene encoding the protein.

In embodiments, the protein is a ZIKV non-structural (NS) protein. In embodiments, the ZIKV non-structural protein is NS5. In embodiments, the protein is NS5 RNA polymerase. In embodiment, the ZIKV non-structural protein is NS2B-NS3. In embodiments, the protein is NS2B-NS3 protease.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a calcium channel blocker.

In embodiments, the calcium channel blocker is manidipine, cilnidipine, or benidipine.

In another aspect, there is provided a method of treating a Zika viral infection. The method includes administering to a subject in need thereof an effective amount of a combination therapeutic composition including an NS5 polymerase inhibitor and a HIV protease inhibitor. The term “combination therapeutic composition” or the like refers, in the usual and customary sense, to administration of a plurality of pharmaceutically acceptable compounds or agents, each optionally including a pharmaceutically acceptable excipient. The plurality of pharmaceutically acceptable compounds or agents can be administered in a single dosage. The plurality of pharmaceutically acceptable compounds or agents can be administered in a multi-dose regimen. The plurality of pharmaceutically acceptable compounds or agents can be co-administered with each other.

In embodiments, the combination therapeutic composition includes Suramin, Ganciclovir, Procaine hydrochloride, Zidovudine, Acyclovir, Drostanolone Propionate, Dapivirine (TMC120), Tilorone hydrochloride, Docosanol, clomiphene, amphotericin B, toremifene, mycophenolic acid, fluoxetine, niclosamide, and/or polyhydroxyalkanoates (PHA).

The following examples illustrate certain specific embodiments of the invention and are not meant to limit the scope of the invention.

Embodiments herein are further illustrated by the following examples and detailed protocols. However, the examples are merely intended to illustrate embodiments and are not to be construed to limit the scope herein. The contents of all references and published patents and patent applications cited throughout this application are hereby incorporated by reference.

Example 1. Screening Studies

As shown in FIG. 1A, antiviral activity of approved drugs/clinical molecules library was tested against Zika virus in human 293 T cells at the MOI of 5. Cells were pretreated with drugs (10 uM) for 1 hour and infected with ZIKV (MOI=5). After 24 hours of infection, mRNA was isolated and the levels of cellular ZIKV was determined by qRT-PCR.

As shown in FIG. 1B, methyl transferase inhibitors potently reduced ZIKV replication. Methods were as described in FIG. 1A.

As shown in FIGS. 2A-2D, there is observed a dose dependent inhibition of selected antiviral molecules. Conditions: Zika virus in 293 T cells at the MOI of 5 using different concentration of drugs. IC₅₀ was calculated.

As shown in FIGS. 3A-3B, there is observed synergistic activity of lopinavir and ritonavir. 293 T cells were pretreated with indicated drugs and after 1 hour, the cells were infected with ZIKV at the MOI of 5. After 24 hours, proteins were analyzed by western blotting (FIG. 3A) and mRNA was isolated and the levels of cellular ZIKV was determined by qRT-PCR (FIG. 3B).

FIG. 4 outlines an experimental protocol to determine the drug efficacy for ZIKV inhibition in vivo.

FIGS. 5A-5D depict results demonstrating ZIKV protease inhibition in animal tissues (i.e., brain, blood, testes, spleen), in prophylaxis (i.p) and therapeutic (oral) regimens.

FIG. 6 depicts ZIKV levels as determined by qRT-PCR for ZIKA in Vero cells at 10 μM concentration (left to right) of control, berberine, fluoxentine, formoterol, genistine, U0126, dibucaine, pirlindole, suramin, mycophenolic acid, PHA, and niclosamide.

FIG. 7 depicts dose response studies on ZIKV levels for clomiphene, amphotericin B, and toremifene.

FIG. 8 depicts ZIKV levels after administration of various agents. The term “Hits” refers to agent which reduce ZIKV load, including Ganciclovir, Procaine hydrochloride. Zidovudine. Acyclovir. Drostanolone Propionate, Dapivirine (TMC120), Tilorone hydrochloride, and Docosanol.

FIGS. 9A-9K depict ZIKA inhibition by various drugs as visualized by immunostaining. Agents in order (top to bottom): mock, DMSO, PHA-690509, formoterol, fluoxetine, genistein, U0126, berberine, dibucaine, pirlindole, and suramin.

Example 2. Zika Virus Infection Reprograms Global Transcription of Host Cells to Allow Sustained Infection

Abstract. Zika virus (ZIKV) is an emerging virus causally linked to neurological disorders, including congenital microcephaly and Guillain-Barré syndrome. There are currently no targeted therapies for ZIKV infection. To identify novel antiviral targets and to elucidate the mechanisms by which ZIKV exploits the host cell machinery to support sustained replication, we analyzed the transcriptomic landscape of human microglia, fibroblast, embryonic kidney, and monocyte-derived macrophage cell lines before and after ZIKV infection. The four cell types differed in their susceptibility to ZIKV infection, consistent with differences in their expression of viral response genes before infection. Clustering and network analyses of genes differentially expressed after ZIKV infection revealed changes related to the adaptive immune system, angiogenesis, and host metabolic processes that are conducive to sustained viral production. Genes related to the adaptive immune response were downregulated in microglia cells, suggesting that ZIKV effectively evades the immune response after reaching the central nervous system. Like other viruses, ZIKV diverts host cell resources and reprograms the metabolic machinery to support RNA metabolism, ATP production, and glycolysis. Consistent with these transcriptomic analyses, nucleoside metabolic inhibitors abrogated ZIKV replication in microglia cells.

Introduction

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family [1,2], which includes West Nile (WNV), yellow fever, Chikungunya, dengue, and Japanese encephalitis viruses [2]. These viruses cause mosquito-borne diseases transmitted by the Aedes genus [2]. ZIKV may also be transmitted sexually and vertically [3,4]. ZIKV was first discovered more than 60 years ago in samples taken from a sentinel rhesus monkey in the Zika forest of Uganda, and has since been isolated from mosquitoes and humans [5,6]. Various epidemiological studies have revealed a worldwide spread of ZIKV to geographic areas ranging from Asia and the Pacific to, most recently, the Americas [1]. The rapid spread of ZIKV from Asia to the Americas has affected more than 30 countries. Due to its sporadic nature and mild symptoms, ZIKV infection was initially ignored. Approximately 80% of ZIKV infections are asymptomatic, and the most common symptoms include fever, arthralgia, rash, myalgia, edema, vomiting, and non-purulent conjunctivitis [7]. However, ZIKV infection in pregnant women has been linked to the increasing incidence of congenital microcephaly and other disorders such as placental insufficiency, fetal growth retardation, and fetal death. Emerging evidence suggests that ZIKV causes mild symptoms in non-pregnant individuals, but it has also been associated with neurological abnormalities and Guillain-Barré syndrome [8-11].

Female Aedes mosquitoes act as vectors to transmit ZIKV through the skin of the mammalian host, which is followed by infection of permissive cells through specific receptors. Current reports indicate that dermal fibroblasts, dendritic cells, neural progenitor cells, and epidermal keratinocytes are permissive to ZIKV infection while placental trophoblasts are resistant due to constitutive release of type III interferon [12-16]. Interferon knockout mouse models have also shown susceptibility to ZIKV infection [17-19]. However, the pathogenesis of ZIKV infection remains poorly understood. In this study, we analyzed transcriptomic changes induced by ZIKV infection in four human cell lines (microglia, fibroblast, macrophage, and human embryonic kidney cells) to identify genes that could be developed as potential therapeutic targets and to provide insight into the interaction between ZIKV and the host cell.

Results.

Cell Type-Specific ZIKV Replication and Infection. To analyze factors contributing to ZIKV pathogenesis, we selected four human cell lines, microglia, BJ (foreskin fibroblast), 293FT (embryonic kidney), and THP-1 derived macrophages (monocyte-derived macrophage), and inoculated them with ZIKV produced in Vero and BHK cells at a multiplicity of infection of 1 (FIGS. S1A-S1E). The choice of cell lines was driven by a desire to understand different aspects of ZIKV pathogenesis. Microglia cells model the resident macrophages in the brain and provide information on how they may contribute to neuroinflammation and other ZIKV-associated neurodegenerative disorders, such as Guillain-Barré syndrome. BJ cells were selected to model dermal infection, the primary route of mosquito-driven ZIKV infection. The 293FT human embryonic kidney cell line is well known for robust lentivirus production and may provide an ideal host for ZIKV replication as well. Lastly, THP-1 macrophages provide a model of the effect of ZIKV infection on a host cell critical for the immune response. ZIKV expression was assessed by immunofluorescent staining of cells with an antibody against the ZIKVE flavivirus envelope protein at 24 h post-infection (hpi). ZIKV infection was most marked in microglia cells, followed by BJ, 293FT, and THP-1 derived macrophages (FIGS. 10A-10D). These findings were confirmed by one-step RT-qPCR of viral RNA in the cell supernatants, which showed statistically significant differences in the levels of viral transcripts between microglia and THP-1 derived macrophages at 24 and 48 hpi (FIG. 10E). This marked difference in ZIKV susceptibility is notable because both cell types are macrophages; microglia cells are microglial and THP-1 derived macrophages are monocyte-derived.

We next analyzed changes in the transcriptomic landscapes of the four cell types after ZIKV infection to identify potential key regulators responsible for the cell type-specific differences in ZIKV replication. For this, total RNA was extracted from mock- and ZIKV-infected cell lines at 24 hpi and analyzed by Illumina NextSeq 500. We elected to examine gene expression at 24 hpi to assess the effects of ZIKV infection immediately following the early innate immune response (FIGS. S1E-S1E). FIGS. 11A-11E show the data presented in Circos plots, in which the fold change for differentially expressed genes (shown in inner circles) are plotted in contrast with the overall gene expression level (in outer circles) for microglia, BJ, 293FT and THP-1 derived macrophages (FIGS. 11A-11D, respectively). Interestingly, the level of ZIKV expression and the impact of ZIKV infection on the transcriptome were inversely correlated. Thus, microglia cells showed the fewest changes in gene expression following infection (FIG. 11A), followed by BJ (FIG. 11B), 293FT (FIG. 11C), and THP-1 derived macrophages (FIG. 11D). Furthermore, the magnitude of the gene expression changes also differed between the cell types, with the differentially expressed genes in THP-1 derived macrophages displaying the biggest differences between mock- and ZIKV-infected cells (FIG. 11E).

Analysis of Viral Response Genes Identifies Potential Cell Type-Specific Regulators. To identify genes that may account for the different levels of ZIKV expression in the four cell lines, we analyzed the expression of endogenous viral response genes before infection. We hypothesized that the initial ZIKV viral entry and replication mechanisms might be dependent on the expression levels of specific host genes. Thus, genes from the human GRCh38.p5 database in Ensembl associated with the following gene ontology terms were analyzed in the mock-infected cells: “response to virus,” “modulation of virus host gene expression,” “viral transcription,” and “viral release from host cell” (FIGS. 12A-12B, FIGS. S1A-S2D, and Table 1).

Consistent with our hypothesis, THP-1 derived macrophages, which were the most resistant to ZIKV infection, expressed the greatest number of viral response genes and immune-related genes, while microglia cells express the fewest (FIGS. S2E-S2F, Table 3). Genes that were uniquely or highly expressed in THP-1 derived macrophages but showed low expression in microglia were analyzed as potential antiviral ZIKV factors. Interestingly, expression of immune regulatory molecules, including CCL3, CCL4, CCL5, TNF, IRF5, CXCL10, OAS1, TLR7, TLR8, and IL27 was highest in THP-1 derived macrophages, indicating that they are primed to mount a vigorous defense as part of the initial innate immune response to ZIKV and to elicit greater transcriptional changes in response to ZIKV infection (FIGS. 11E and 12B). Comparison of genes differentially expressed in the four cell types before infection revealed high expression of CD4 in THP-1 derived macrophages and low expression of CHMP4C (charged multivesicular body protein 4C). CHMP4C is a component of the ESCRT-III family responsible for surface receptor degradation and viral budding [20]. Further mechanistic studies will be necessary to determine which of these viral response and immune-related genes might be vital for regulating ZIKV expression.

We also examined the differential expression of cell surface receptor genes in the four cell types prior to ZIKV infection to identify potential antiviral receptors that may confer greater ZIKV resistance on THP-1 derived macrophages. Heat map clustering of cell surface receptor genes identified several genes that were expressed highly in THP-1 compared with the other cell types, including CD86, LY6D, CXCL10, CD48, and IL12RB1 (FIGS. 12C-12D, Table 2). Gene ontology analysis of these and other genes showing selectively high expression in THP-1 derived macrophages revealed an enrichment of genes involved in cell activation, immune response, and cell receptor signaling (FIG. 12E). These analyses of the steady-state expression of endogenous genes in the four cell lines before ZIKV infection have identified a number antiviral genes highly expressed in THP-1 derived macrophages, suggesting they could be exploited to therapeutic effect.

ZIKV Infection Modulates the Metabolic and Transcriptional Landscape. To determine the effects of ZIKV infection on the host transcriptome, we analyzed differentially expressed genes between mock- and ZIKV-infected cell lines at 24 hpi. As mentioned above, the total number of differentially expressed genes in ZIKV-infected cells was inversely correlated with the level of ZIKV infection, with the least and most marked changes occurring in CHME-1 and THP-1 derived macrophages, respectively (FIGS. 10A-10E and 11E). In-depth analysis of the differentially expressed genes revealed that ZIKV infection elicited a similar pattern of gene expression changes between BJ and 293FT cells and between microglia and THP-1 derived macrophages, both macrophage cell types; however, the fold change in expression is much greater in THP-1 derived macrophages (FIG. 13A, Table 4). Predictive network analyses suggested that a significant portion of the differentially expressed genes following ZIKV infection interact to regulate common pathways such as including mRNA processing, metabolic processes, RNA processing, and cellular component disassembly (FIG. 13B and FIGS. S3A-S3D).

Further clustering analysis highlighted the distinct patterns of gene expression changes in the ZIKV-infected cells (right vertical bar in FIG. 13A). Analysis of genes that were predominantly upregulated in microglia and THP-1 macrophages and downregulated in BJ and 293FT cells (red on the vertical bar in FIG. 13A) indicated that they are associated with transcriptional regulators, RNA metabolic processes, and macromolecule biosynthesis (FIG. 13C). Genes upregulated in THP-1 macrophages and downregulated in all other cell lines (green bar) included IL1B, CD4, IL27RA, and FCER1G which act as positive regulators of the adaptive immune response, Fc epsilon RI signaling pathway and complement and coagulation cascades (FIGS. 13A and 13E). Interestingly, these genes are downregulated in microglia, BJ, and 293FT. These findings help to explain why THP-1 derived macrophages, which have the highest expression of innate immune genes in the uninfected state and the greatest upregulation of adaptive immune response genes post-infection, have the lowest level of ZIKV expression.

The cluster of genes downregulated by ZIKV infection in microglia and BJ but upregulated in 293FT and THP-1 derived macrophages (bar, FIG. 13A) included several key genes that regulate virus receptor activity, protein kinase B activity, and angiogenesis (FIG. 13F). A notable gene in this cluster is the viral entry receptor AXL, which has previously been associated with ZIKV pathogenesis [12,21]. In contrast, the gene cluster downregulated in the macrophage lines (bar in FIG. 13A), and particularly in THP-1 derived macrophages, are strongly associated with translational elongation and various cellular metabolic processes (FIG. 13D). Finally, genes differentially expressed in ZIKV-infected microglia and THP-1 derived macrophages (bar in FIG. 13A) were related to metabolic processes (FIG. 13G). Viruses are obligate parasites that exploit the host's metabolic processes to reproduce [22-24]. Understanding the mechanisms by which ZIKV alters the host cell metabolism may thus provide additional novel therapeutic targets. Further examination of the roles of metabolic control genes such as TERT, ALDH7A1, CREB5, EAPP, and NDUFA11 as they relate to ZIKV infection may provide further insights into ZIKV pathogenesis.

Since metabolic processes are the most dysregulated pathways during ZIKV infection at the transcriptome level, we hypothesized that inhibition of these pathways could be exploited for therapeutic effects. To determine the role of host cell metabolism in ZIKV replication, we utilized nucleoside metabolic inhibitors because nucleoside analogs have been reported to inhibit flaviviruses by interfering with RNA synthesis, methyl transferases, and thymidine synthesis pathway [25-27]. We utilized nucleoside metabolic inhibitors flurouracil and floxuridine in our experiments. Microglia cells were treated with flurouracil or floxuridine and inoculated with ZIKV. The effect of the antimetabolites floxuridine (FIGS. 14A-14B) and flurouracil (FIGS. 14C-14D) on ZIKV replication was assessed 48 hpi at the RNA and protein level by RT-qPCR and immunohistochemistry, respectively. Although both nucleoside analog affected ZIKV, but the treatment of floxuridine inhibited ZIKV more efficiently in a dose dependent manner than flurouracil. These findings show that ZIKV replication is sensitive to nucleoside metabolic pathways revealed by transcriptomic analyses.

Discussion.

We analyzed the transcriptional profiles of human microglia, fibroblast, kidney, and macrophage cell lines to explore the host factors that contribute to susceptibility to ZIKV infection, viral replication, and host symptomology. ZIKV expression was significantly different among the cell lines, with a notably large difference between microglial cells and THP-1 monocyte-derived cells, despite both being macrophage cell lines. A recent study analyzing the cell line susceptibility in across cell types—including placental, genitourinary, neuromuscular, retinal, respiratory and liver—and species further validate our findings. Similar to our results, the study showed that THP-1 derived macrophages are relatively resistant to viral infection when compared to HEK, HeLa and SF268 neurons [28].

By analyzing steady-state gene expression levels in cells before ZIKV infection, we identified several antiviral response genes that may contribute to the significant difference in ZIKV expression between cell types. For example, the Toll-like receptors TLR7 and TLR8 are functionally related genes and are highly expressed in THP-1 derived macrophages compared with microglia, 293FT, and BJ cells. Since TLR7 and TLR8 are activated by ssRNAs, they likely allow THP-1 macrophages to recognize flaviviruses and produce a more robust innate immune response [29-30]. Moreover, THP-1 derived macrophages express TNF-α as well as CD86, a co-stimulatory molecule that has been implicated in the early and late acute phases of dengue infection. However, it is important to note that differences in basal level gene expression between cell types does not necessarily equate to functional significance. Further experiments will be required to determine which of these antiviral response genes regulate ZIKV expression.

Other flaviviruses, such as West Nile (WNV), dengue, yellow fever, and Japanese encephalitis viruses, have shown a remarkable ability to evade the innate and adaptive immune systems [31]. Complement proteins recognize target pathogens and act as opsonins to promote recruitment of phagocytes and lysis of infected cells. Previous studies have shown that the complement system can be compromised by the flavivirus nonstructural protein NS1, which interacts with the complement regulatory glycoprotein factor H [32]. In addition, flaviviruses are able to evade the antibody and cellular immune response by affecting antigen presentation. The error-prone nature of flavivirus RNA polymerases leads to the accumulation of mutations and subsequent alterations in viral proteins that may help them to escape recognition by neutralizing or inhibitory antibodies [32].

We showed that ZIKV affects the adaptive immune response and complement cascade by modulating genes such as IL1B, CD4, IL27RA, and A2M. Flaviviruses downregulate CD4 mRNA through an NS5-dependent mechanism, thereby dysregulating both the innate and adaptive immune systems [33]. Moreover, these findings are corroborated by a recent study analyzing transcriptional changes in ZIKV infected human neural stem cells in which leukocyte activation, cytokine production and defense response pathways were significantly dysregulated [34]. In addition, IL1B has previously been linked to WNV. IL-1β is present at increased levels in the plasma and cortical neurons of WNV patients, and it plays a key role in restricting virus replication [35]. IL-1β acts in concert with type I IFN and the NLRP3 inflammasome to restrict WNV replication. Interestingly, IL1B expression was upregulated by ZIKV in THP-1 derived macrophages cells but downregulated in microglia cells, which is consistent with our finding that viral replication is higher in the microglial-derived than in the monocyte-derived macrophage. These data imply that, while ZIKV is actively targeted by the innate and adaptive immune responses via monocyte-derived macrophages, it is able to effectively evade the microglial immune response once it passes through the blood-brain barrier and reaches the central nervous system.

Endothelial cells are one of the cell types infected by dengue, also a flavivirus, and the breakdown in endothelial barrier function causes the vascular leakage associated with hemorrhagic fever. Dengue virus type 2 suppresses TNF-α-mediated hyperpermeability and angiogenesis by modulating type I IFN [36]. Cases of thrombocytopenia and subcutaneous bleeding have been observed in ZIKV patients [37]. Our data suggest that ZIKV may affect angiogenesis and endothelial cell integrity. These findings may provide insights into the molecular mechanisms by which ZIKV passes through the blood-brain barrier.

We identified a large number of differentially expressed genes associated with cellular metabolic processes following ZIKV infection. Previous studies have drawn attention to the role of viral-mediated reprogramming of host metabolic processes in pathogenesis. In accordance with our findings, transcriptional alterations in human neural stem cells inoculated with MR766 strain ZIKV revealed significant remodeling of nucleic acid metabolic processes and macromolecule biosynthesis [34]. RNA viruses such as influenza and dengue alter fatty acid synthesis and induce glycolysis to promote viral replication, late gene synthesis, and virion assembly [22]. The role of dengue NS3 recruitment of fatty acid synthase to sites of viral replication has been dissected using RNAi and small molecule inhibitors in an effort to identify potential therapeutic targets [38]. Many other viruses redistribute host cell resources to promote viral replication by altering the localization of lipids, as seen with dengue. In addition, viral infection alters the rate of host RNA metabolism to enhance the availability of nucleotides [24].

The molecular mechanisms by which viruses redirect cellular resources and exploit the host metabolic machinery are largely unknown. Recent work showed that the adenovirus gene element E4ORF1 upregulates glucose metabolism by altering the epigenetic landscape. E4ORF1 interacts with MYC to enhance transcription of glycolytic enzymes and nucleotide biosynthesis [39]. Here, we identified several genes associated with metabolic regulation that are differentially expressed between cell types following ZIKV infection, including CREB5, TERT, CNIH1, ADAM12, and USE1. One gene that ZIKV may exploit to regulate the host cell is CREB5. CREB5 (CAMP-responsive element-binding protein 5) is a transcription factor that regulates nucleotide and nucleic acid metabolism, transcription, and signal transduction, and is also highly upregulated in patients with HIV encephalitis and vaccinia virus infections [40,41]. Because cellular metabolism is often a limiting factor in viral replication, nucleoside/nucleotide-based therapeutics have been developed against a variety of viruses, including HIV, HBV, HCV, HSV, and VZV [23]. Indeed, nucleoside analogs including floxuridine, also known to be effective against other flaviviruses such as dengue, displayed dose-dependent inhibition of ZIKV replication [25-27]. Further mechanistic studies will be required to gain a better understanding of how ZIKV hijacks the host cell metabolic machinery and to aid in the development of ZIKV-targeted therapeutics.

Conclusions. ZIKV infection is an emerging disease associated with increased incidence of neurological disorders including congenital microcephaly and Guillain-Barre syndrome. Here we analyzed the transcriptomic changes associated with ZIKV infection across multiple cell types to identify novel therapeutic targets and understand the host-pathogen interaction for sustained ZIKV replication. The response to ZIKV is cell type specific with the greatest replication found in microglia cells. ZIKV is highly expressed in microglia and downregulates immune response genes while high expression of viral response genes in macrophages confers ZIKV resistance. In addition, ZIKV reprograms the host metabolic processes to enhance virus replication through the upregulation of glycolysis and RNA metabolism related genes. Antimetabolites floxuridine abrogated ZIKV replication through inhibition of host nucleoside metabolic pathways. These results reveal that thymidine synthesis pathway can be exploited to develop novel therapeutics to treat ZIKV infections.

Materials and Methods.

Cell Lines and Culture Conditions. Vero, microglia, THP-1, BJ, and 293FT cells were maintained under standard culture conditions at 37° C. in a 5% CO₂ atmosphere. Vero cells, derived from African green monkey kidney cells, were maintained in EMEM supplemented with 10% (vol/vol) fetal bovine serum (FBS) and antibiotics. THP-1 cells, a human leukemia monocytic cell line, were cultured in RPMI 1640 medium supplemented with 10% FBS and 50 μM β-mercaptoethanol (Sigma). THP-1 cells were differentiated into macrophages by treatment with 5 ng/ml phorbol-12-myristate-13-acetate (PMA) overnight. The following day, the medium was replaced with fresh medium without PMA. 293FT human embryonic kidney cells and the human fibroblast cell line BJ were cultured in DMEM (Invitrogen) supplemented with 10% FBS. The human microglial cell line was cultured in DMEM medium with high glucose supplemented with 10% FBS and 1% penicillin/streptomycin.

Zika Virus Propagation and Infection of Cell Lines. ZIKV prototype MR766 was propagated in the low passage Vero cell line. Vero cells were infected with virus at a MOI of 1 in EMEM medium supplemented with 10% FBS. The medium was replaced with fresh medium 24 h after infection and the viral supernatant was collected at 48 h post-infection. Viral titers were assessed using iScript One-Step RT-PCR kit (Bio-Rad) and the viral copy number was calculated from a standard curve of in vitro transcribed viral RNA transcripts. For infection, cell lines were seeded in 6-well culture plates at a density of 1×10⁶ cells per well. ZIKV, diluted to the desired multiplicity of infection (MOI:1), was added to the cells, and the plates were incubated at 37° C. in a 5% CO₂ atmosphere for 6, 12, 24, or 48 h. As controls, cells were incubated with culture supernatants from uninfected Vero cells (mock-infected controls). At the indicated times post-infection, cell supernatants were collected for determination of viral copy number.

Immunofluorescence Microscopy. To assess ZIKV infection, cells were harvested at 24 h following infection and immunostained as described previously [16]. ZIKV- and mock-infected cells were fixed with 4% paraformaldehyde in PBS for 20 min at room temperature. Cells were blocked by incubation in 3% BSA and 0.1% Triton X-100 for 2 h at room temperature and then incubated overnight at 4° C. with ZIKVE/anti-flavivirus group antigen antibody (1:500, mouse, Millipore MAB10216), which is directed against the flavivirus envelope protein. Cells were washed with PBS and incubated for 2 h at room temperature with fluorescein isothiocyanate (FITC)-conjugated anti-mouse IgG. The nuclei were stained with Hoechst 33258. Immunostained cells were imaged using a Leica fluorescence microscope (DMI 3000B).

RNA Extraction, cDNA Synthesis, and qRT-PCR. For cellular mRNA analysis, RNA was extracted from the cell lines using an RNeasy Mini Kit (Qiagen), following the manufacturer's instructions. RNA samples were treated with RNase-free DNase (Qiagen) and cDNA was generated from total RNA (500 ng/sample) using iScript Mastermix (Bio-Rad), according to the manufacturer's instructions. qPCR was performed with SYBR Green PCR Master Mix (Bio-Rad) using a Roche LightCycler 480.

RNA-Seq and Data Analysis. For RNA-seq analysis, RNA was extracted from the cell lines using an RNeasy Mini Kit (Qiagen), following the manufacturer's instructions. RNA was ribo-depleted, and RNA sequencing was performed using an Illumina NextSeq 500 with an average of 20 million reads per sample at The Scripps Research Institute NGS Core facility. The single-end reads that passed Illumina filters were filtered for reads aligning to tRNA, rRNA, adapter sequences, and spike-in controls. The reads were then aligned to UCSC hg19 reference genome using TopHat (v 1.4.1). DUST scores were calculated with PRINSEQ Lite (v 0.20.3), and low-complexity reads (DUST>4) were removed from the BAM files. The alignment results were parsed via the SAMtools to generate SAM files. Read counts to each genomic feature were obtained with the htseq-count program (v 0.6.0) using the “union” option. After removing absent features (zero counts in all samples), the raw counts were imported into R/Bioconductor package DESeq2 to identify differentially expressed genes among the samples. DESeq2 normalizes counts by dividing each column of the count table (samples) by the size factor of this column. The size factor is calculated by dividing the samples by the geometric means of the genes. This brings the count values to a common scale suitable for comparison. P values for differential expression were calculated using binomial test for differences between the base means of two conditions. The p values were adjusted for multiple test correction using the Benjamini-Hochberg algorithm to control the false discovery rate. Cluster analyses, including principal component analysis and hierarchical clustering, were performed using standard algorithms and metrics. Gene ontology analyses on biological processes were performed using The Database for Annotation, Visualization and Integrated Discovery (DAVID) [42]. Grouped functional pathway/gene ontology network analyses were performed using Cytoscape with the ClueGo add-on [43,44]

Drug Treatment. Human microglial cell line was infected with ZIKV virus at MOI of 1 in cell medium containing metabolic inhibitors such as 5-Fluorouracil (Abcam, ab142387) and Floxuridine (Tocris, 4659) in cell medium containing 1 μM and 10 μM of each drug or 1% (vol/vol) DMSO as a control. After 48 h post-infection cellular RNA was extracted using Trizol and cDNA was synthesized by iScript Mastermix (Bio-Rad), as per manufacturer instructions. ZIKV RNA was quantified by using specific primers by SYBR Green PCR Master Mix (Bio-Rad) using a Roche LightCycler 480. Further immunocytochemistry for was also performed in microglial cells for detection of ZIKV infection using flavivirus group antigen specific antibody (Millipore).

Tables (Example 2).

TABLE 1 Gene expression of viral response genes, Related to FIG. 12A. Values represent log2(RPKM + 1). Associated Gene Name chme bj 293 thp1 FGF7 1.91838623 8.84830996 1.81557543 3.26603689 LMCD1 6.15845822 8.36181222 6.39351917 0 COX8A 10.947615 10.229648 9.97955381 10.9550105 DKKL1 2.49313492 1.79493566 3.35473424 1.28688115 MSTN 0 1.79493566 1.422233 1.95233357 CHAF1B 9.49215363 8.46107011 9.55939621 4.58436125 ATP1B1 10.3670652 9.31286027 8.45145841 8.03606369 HIST1H3D 11.284211 11.5114908 5.00225245 7.62811741 C1orf210 0 0 1.422233 3.03210084 SNTG1 0 1.79493566 0 4.07038933 IST1 11.6720452 10.662793 10.3900292 11.5676567 FABP1 #N/A #N/A #N/A #N/A TMEM173 7.41438927 9.43352285 4.79960542 8.9561438 MYOM1 2.23572706 3.59693514 3.23112516 4.66789213 CCDC36 0 5.20006486 0 1.28688115 CRNKL1 10.3861751 10.094632 9.94436068 9.58535693 FXR2 10.8262068 10.6294932 10.1533114 10.6784857 DNAAF2 7.86795822 7.9518675 8.61787147 8.49257426 RFWD3 11.3086633 10.9240331 11.15108 9.82815236 CA7 1.51096192 0 2.12432814 2.40871186 PDK4 3.0721058 1.79493566 5.24488706 3.26603689 ALPK1 6.46123386 7.93740325 6.89857116 6.90989308 STOM 9.37623394 11.4517778 8.6209529 12.2645511 MDH1 10.5881524 11.4125116 11.2513226 11.7651866 FCGR3B #N/A #N/A #N/A #N/A REEP2 7.90189263 7.62234472 9.23713824 3.03210084 EIF2AK4 10.3569141 11.5960919 10.0255687 9.84403094 HILPDA 7.66554911 7.26575568 8.00045077 6.66633054 SERPINB10 0 1.79493566 1.422233 1.95233357 MRPS10 10.4668004 10.2147562 9.96266469 12.2783856 CD163L1 0.94860085 5.50430258 1.422233 4.39985467 CREB3 10.3218267 10.6539915 7.93769749 10.6568271 DDX58 8.49785184 8.61871585 7.05245937 8.41578401 LILRB1 0 0 0 5.08915913 PHYHIP 3.36036428 3.73660488 1.422233 4.18903382 MB21D1 8.92389197 8.76081973 2.37851162 8.90517638 KCNQ1 0.94860085 0 2.592158 5.79701298 YIPF1 8.87347487 8.13386145 8.08316017 9.63314055 UBA52 12.4517881 12.1573375 12.2104765 12.7400485 SMURF1 9.49956689 9.78558325 8.50910199 10.0958585 CPA3 5.62029315 0 0 1.28688115 ASB2 0 0 1.81557543 3.46727948 CLDN7 2.49313492 2.56803211 3.46858332 6.92706681 PNPO 7.40658769 8.43562859 8.51573926 10.053573 MAP1A 9.7927415 12.2052098 9.60829179 4.82273015 MBD5 7.00999653 7.59507095 6.78240857 7.2465981 ZNF681 0 5.15055968 5.39643353 0 SLC35B3 9.34777637 9.63041275 7.60607203 8.52109001 HCAR1 1.51096192 0 0.87970577 0 MAVS 9.78517453 10.0617222 9.2806084 8.62972089 KIAA1549L 7.11019618 9.65266575 6.03584382 4.29865832 PTPN22 5.95814667 3.59693514 1.81557543 6.64573048 ITPKC 7.21286112 7.94462422 6.67990229 7.91247024 SLC25A19 5.28540222 5.88141991 7.65492239 7.50803243 FGF14 0 7.25417829 0 0 PYDC1 0 0 1.422233 0 MRPS2 8.6520562 8.15896306 9.26886945 8.04395687 HIST1H3F 12.025977 11.984625 10.4141884 6.78384949 IL12B 0.94860085 0 0.87970577 1.28688115 C8orf59 6.64616266 6.92872562 6.2890967 7.20506011 FAM13B 9.62338771 10.0995056 9.40367249 10.1442886 ACKR3 6.02125762 4.09000653 0 7.85990745 LSM4 11.3165474 10.7208599 11.1590451 11.0312739 PPY 0 0 0 0 EIF2S1 11.6551461 11.8982537 11.688753 11.675516 HIST1H3H 11.6241375 11.4788303 12.0773131 7.2465981 ANXA5 13.4499882 13.8543191 11.323477 14.4576502 GABRA5 0.94860085 1.15704371 0.87970577 0 HPR 0.94860085 0 0 0 ACIN1 11.1046119 11.164643 11.2730088 10.7512428 CHST3 11.3399502 11.3600185 8.68706069 6.68664059 SLC1A3 8.26129574 1.15704371 9.60518317 12.6957459 SIN3A 9.49215363 9.52085436 10.3320477 8.94356975 SCN1A 0.94860085 1.15704371 0 0 CD93 0.94860085 1.15704371 1.422233 2.40871186 LENG9 5.21490191 5.61735726 4.45811948 5.59723319 TEAD4 8.39835892 7.98732087 9.01881219 5.6395216 HIST1H3A 9.86046626 10.4478478 11.1516128 5.26115467 TREM1 0.94860085 2.23266076 0 6.32228872 RBM18 9.54502237 9.61687962 9.04884103 9.65644274 IL23R #N/A #N/A #N/A #N/A PEX3 8.87347487 8.67200096 8.47889093 7.54179359 AIM2 0.94860085 1.15704371 0 6.00495076 STAT2 10.0875557 10.5174529 8.69289443 9.9836492 PEX13 9.29980329 10.0263436 8.86635166 10.6309132 HIST1H3I 8.67514551 9.77140693 9.32280697 5.68060567 ALKBH5 11.1269045 11.0136577 11.8788211 10.4953354 HIST1H3J 10.017045 10.8860014 9.73443867 5.26115467 CSPG5 2.49313492 3.4409522 7.30295873 4.29865832 DPF3 4.21800615 7.33351318 5.58466191 8.22804905 MYLK 12.3154808 13.9034375 7.62461271 8.09032418 TMEM39B 7.7548875 7.20672136 7.19140473 6.97727992 SUPT3H 6.68565988 5.9112122 7.33333428 6.83920379 PML 7.87369018 8.58202905 7.55550943 7.27360913 MTSS1 4.41886458 5.8509994 7.07948478 13.0445615 HIST1H3G 11.0092338 11.4248591 0 5.36562256 SNRPD1 10.5449451 10.1315741 10.9788391 9.58805872 IL4 0.94860085 0 0 0 NUP93 11.3685447 10.5999965 11.0762478 9.70691038 FAM131B 4.84799691 5.29351763 5.0395771 5.97223312 HIST1H3C 11.4677074 11.5582485 0.87970577 5.90472493 TRAF3IP2 8.76085299 8.63669712 6.55673595 8.52109001 KRT6A 0 0 0 0 ZNF189 8.95921954 8.80522796 8.99052948 9.05688153 SNRPB2 10.1358888 10.1814505 10.2299003 9.37046946 HIST1H3E 10.3039519 11.3313089 6.70334992 2.7548875 NTHL1 7.72996056 7.66682759 8.93966736 6.70653055 FANCL 8.05555359 8.21989453 8.69289443 7.75828985 SELK 8.92389197 9.06638524 8.89965903 9.83724947 HIST1H3B 12.8031463 12.435876 12.8302478 6.09866378 SNRPB 11.6342711 11.2334879 12.1488992 10.863412 IL12RB1 0 0 1.422233 5.75915583 GMIP 6.19554446 7.15775114 6.67990229 9.95261022 ZCCHC17 9.18735207 8.64562241 8.87408995 8.33463084 IL23A 2.71369582 1.15704371 2.94673086 3.80012335 SLC35C1 8.58747751 8.84058912 6.54380518 6.80258099 FGFBP1 1.51096192 0 2.12432814 0 TMEM39A 9.82553125 9.59172803 8.60547952 9.66666784 TNIK 10.1167468 9.30724636 9.04884103 8.12789118 TRIM6 7.2917693 6.54643149 6.70334992 1.95233357 TMEM203 9.40609869 9.12174071 8.81618368 9.55537521 ACTRT1 #N/A #N/A #N/A #N/A APOBEC3G 1.91838623 4.81403765 3.93168306 8.09032418 APOBEC3F 3.89724043 5.46434153 5.36737107 5.14893411 REP15 2.49313492 3.07038933 2.12432814 4.18903382 SLC37A4 6.6055536 7.34447346 9.15881163 7.13298804 TLR3 3.22342255 2.56803211 5.75114233 2.7548875 SERINC5 6.73674016 6.94333532 6.79337571 7.14771372 SERINC3 11.7797768 12.2324509 10.3737026 11.9367852 IFIH1 6.10118782 4.68144927 6.2890967 8.77402928 MX1 5.86937792 5.38162947 2.94673086 2.40871186 CCL4 0.94860085 0 0 11.6060674 MX2 5.93640238 3.73660488 1.422233 5.55397481 OAS2 2.49313492 3.73660488 1.81557543 8.02020215 LAMTOR5 9.41591074 9.4514172 8.81082866 10.8101539 HYAL1 0 1.79493566 2.12432814 2.7548875 BATF3 5.38474059 4.74899785 5.83844759 4.18903382 CXCL12 9.75764002 10.6726375 5.0395771 2.7548875 OASL 2.49313492 2.56803211 0.87970577 6.58225491 FGR 2.23572706 0 0 11.7326677 CHUK 10.3640252 10.2676645 10.3936371 10.298727 RSAD2 0 1.15704371 0 6.58225491 HYAL3 5.17871464 5.88141991 5.65849714 6.90989308 TRIM22 6.65949648 9.88676351 0.87970577 6.26959425 IRF7 7.00999653 5.42357817 6.33467553 10.1696996 TBK1 9.82257083 9.62815387 9.10268437 10.9339783 TNF 1.91838623 1.15704371 0 10.4852457 AP1S1 10.8690077 10.6964112 9.22908316 11.2865809 XPR1 10.077697 10.1140286 9.66902677 10.6973325 FOSL1 9.22804905 9.71748794 1.422233 7.21897486 OAS1 2.23572706 0 0 7.84197312 BTBD17 0 0 0.87970577 0 SRC 8.6218321 9.06638524 8.17397689 10.5830734 PIM2 8.03529399 7.31124879 8.23950306 7.02580399 CCDC130 8.57353359 8.18363538 7.7977912 9.28000515 CXCL10 0 0 1.422233 4.58436125 CFL1 13.9592802 13.6097536 11.9441776 13.4709181 IFNGR2 9.79122802 9.64158215 8.57723998 12.7119014 IL12A 4.06608919 4.68144927 3.46858332 3.26603689 ABCE1 11.258248 11.8019064 12.815041 11.4074908 IFNB1 0 0 0 1.95233357 HMGA2 8.47549026 11.4403034 9.72159482 10.8711814 ENO1 15.4215356 14.5200962 14.9424746 14.3163622 EIF2AK2 9.78821261 10.8087712 10.7221757 9.90151557 OAS3 7.35032044 7.33351318 7.90267659 9.60679383 IFNAR2 6.78607355 6.15542543 5.77346893 8.27565895 CCL11 #N/A #N/A #N/A #N/A NPC2 9.49215363 10.0399198 8.26336311 11.8685795 DUOX2 0 1.15704371 0 3.26603689 CYP1A1 0.94860085 1.15704371 3.76447355 2.7548875 DDX1 10.6207788 11.4943306 11.5147535 10.2904682 CCL22 0 0 1.422233 2.40871186 CCL19 0 0 0 0 XCL1 0.94860085 0 3.35473424 0 DCLK1 8.25252352 6.86913112 6.30451104 1.95233357 SPACA3 #N/A #N/A #N/A #N/A MST1R 2.90496572 1.79493566 4.28243981 1.95233357 IFNGR1 10.3961338 10.0550519 9.16093027 11.5267975 APOB 0 1.15704371 0 1.95233357 URI1 10.6814668 10.3571781 10.1156159 10.0280027 CXCR4 2.23572706 0 8.25941374 8.49833066 CCL8 0 0 0 3.03210084 DDX60 6.94637997 7.74355536 7.03408363 9.36732738 IFITM1 2.23572706 7.24241196 3.76447355 3.03210084 BCL3 6.35102755 5.04701482 3.09592442 7.47346224 CCT5 13.1552831 12.8278726 13.2009691 13.7841052 IFITM2 1.91838623 8.35098337 6.24184018 7.48502423 EEF1G 0 0 0.87970577 3.03210084 HSPB1 10.4060243 11.1975853 7.42071818 9.81440622 TNFSF4 3.7059779 6.63865312 3.35473424 5.14893411 HNRNPUL1 12.1079232 11.517571 11.5213551 11.0391727 BCL2L1 9.4526325 10.627242 8.19888699 10.1277107 BANF1 9.31036284 8.77712378 8.49908847 8.49257426 CCL5 1.51096192 1.15704371 0 9.60145511 IFIT3 9.00419237 8.9050861 3.67242534 9.4257614 BST2 0 1.79493566 2.592158 10.5279852 IFIT1 7.04078287 9.19942697 6.97750891 8.02818235 CLU 6.74926608 7.79246496 9.73159057 3.03210084 IFIT2 7.04078287 8.10181813 2.7803101 7.00977264 ACTA2 9.30193054 10.2132622 3.46858332 0 CREBZF 9.51244419 9.92934719 10.0622756 9.34837408 DHX58 3.89724043 5.9692426 3.57410151 6.96069704 IFNK 0 0 2.12432814 1.28688115 HMGA1 9.49401552 12.4400438 11.3073261 13.6423293 ISG20 3.0721058 3.98185265 3.67242534 7.64896869 RPS15A 10.9209632 10.658399 10.8666144 10.7306569 CHRM2 0 9.35149141 0 2.7548875 IVNS1ABP 11.6956155 11.3667703 10.0092268 12.5226821 PSMA2 9.02231232 8.37794796 8.84805952 8.59797804 ADAR 12.0362011 12.0329687 12.4456486 13.1433976 DDX3X 13.0981851 13.2568603 13.2517457 13.2024223 FOXP3 0 1.15704371 2.37851162 0 CDK6 12.4787418 12.8081658 11.9039948 13.620772 IKBKG 7.63894267 7.44997399 5.96000193 7.97973957 HYAL2 8.46797229 9.06971828 8.04701482 8.90517638 IFI44 6.54951516 6.52732061 0.87970577 7.07274895 IFITM3 8.6013251 9.72171443 5.27649667 7.58563861 ZC3HAV1 10.644361 10.9539345 10.6380738 10.4707097 MEF2C 3.22342255 6.86913112 8.35124846 10.6296116 ODC1 11.7513599 12.1094324 12.6198073 12.3178931 TPT1 12.6331996 13.4574155 12.0984467 14.34214 DDX21 13.0513874 12.7507363 13.4345175 12.656798 PRKRA 9.30827076 9.37577797 9.2806084 8.96448527 TLR8 0 0 0 2.7548875 IFNAR1 10.5864082 10.5403315 9.47002838 11.8746664 TBX21 0.94860085 0 2.94673086 6.21470767 DHX36 10.0286106 10.2266891 9.91956355 9.75087444 IRAK3 5.10265813 8.20789285 3.23112516 8.65051327 IFNW1 #N/A #N/A #N/A #N/A STMN1 13.5339952 12.7048482 11.8100253 9.00135189 IFNG #N/A #N/A #N/A #N/A IKBKB 9.50694225 9.61006514 8.83753333 10.2330684 IFNA17 #N/A #N/A #N/A #N/A IFNA4 #N/A #N/A #N/A #N/A IFNA7 #N/A #N/A #N/A #N/A MYD88 7.21286112 8.38331549 5.14567746 8.42181238 GTF2F1 11.1785777 10.5486678 10.5846807 10.9736902 GATA3 1.51096192 2.83995959 6.78240857 2.7548875 LSM14A 10.6190828 10.4038855 10.5688302 10.6164661 IRF3 9.48284828 8.96327181 8.63622583 10.1015293 TSPAN6 8.47175649 8.80125568 11.0587629 6.99356115 C1QBP 11.8386406 11.5053848 12.9290161 11.5456402 TKFC #N/A #N/A #N/A #N/A BIRC3 7.71094416 6.79103262 4.84247606 10.1146794 BIRC2 11.2761477 12.3209838 9.54486786 11.0558247 NLRX1 7.11019618 7.8242587 8.33632803 8.34739991 ITCH 11.5565013 11.4949456 10.9094131 11.7876414 IL2RA #N/A #N/A #N/A #N/A PCBP2 9.58560105 9.79762911 10.7721743 8.84784036 TRIM38 6.6727082 8.63223186 7.06156021 9.55261147 HTRA1 13.2552086 10.7355391 6.71493235 2.40871186 PPM1B 8.91835642 9.37042587 9.26101359 9.31621364 TRAF3IP1 8.53799488 8.44584255 8.72471848 7.70963528 ELMOD2 9.2457666 10.1092038 10.5672336 8.45762712 TRAF3 10.0311774 9.79962161 9.70283067 10.746422 SPN 0.94860085 0 0 9.86418615 HERC5 4.84799691 3.59693514 9.2451486 5.90472493 TSPAN32 1.51096192 3.07038933 1.422233 2.7548875 IL27 0 1.15704371 0 2.40871186 MICB 8.41019692 9.07301685 7.6368421 8.75495429 TARBP2 8.69783636 8.72342204 9.09384008 8.97275009 MUL1 9.57161993 9.40230862 9.13962809 9.01343434 AP1B1 10.9651061 10.8008109 10.7907476 10.6746866 B2M 14.1453511 13.7308809 11.1758863 15.6891367 HLA-A 11.5759032 10.9130016 8.93224429 13.0366888 AP2A2 10.3039519 10.1220256 10.0486231 10.0398649 AP2S1 11.6245625 11.2835862 10.4817793 12.3767603 ATP6V1H 9.97780939 10.5698841 9.32658678 12.4618887 ELMO1 0.94860085 0 5.24488706 6.72628629 CD4 3.80426012 3.59693514 4.00898878 7.98788928 HCK 0.94860085 1.15704371 0.87970577 8.66590436 AP1G1 12.0285415 11.3388812 11.3749797 11.4143417 PACS1 9.42177031 9.81944466 7.71376454 7.83289001 AP1S3 6.19554446 7.06781078 7.50969584 6.78384949 CD247 1.91838623 0 0 0 AP2A1 10.6105543 11.003293 9.65708617 10.1822454 PAK2 11.6732737 10.9102305 10.1437148 11.3766409 CD8B 0 0 0 1.28688115 DOCK2 8.04039932 7.52911816 0 11.6252203 ARF1 13.1377373 12.6516572 12.0314945 13.3603574 LCK 0 0 0 0 AP2B1 10.2718715 11.4875286 11.6417944 10.3583545 CD28 1.91838623 1.15704371 0 0 AP1S2 10.4010822 10.0074618 9.44594598 13.4173607 RAC1 11.475242 11.417726 10.433575 10.2671144 AP1M2 1.91838623 1.15704371 4.34340782 0 AP2M1 13.8235722 13.1254829 11.2958148 12.4415385 AP1M1 10.6976626 9.91466916 9.70137578 9.70194752 FYN 11.0463737 9.22937162 9.92331263 9.48480276 TNFAIP3 9.14072754 8.30108459 6.30451104 10.5349934 RNF216 10.6992688 10.3380678 10.0474784 9.81440622 IFNLR1 2.23572706 0 7.65492239 1.95233357 IL15 5.84624257 6.07852445 3.35473424 2.7548875 PM20D1 1.91838623 3.07038933 3.46858332 1.28688115 USP17L2 0.94860085 0 1.81557543 0 IFNA13 #N/A #N/A #N/A #N/A NCBP3 #N/A #N/A #N/A #N/A ITGAX 1.91838623 0 2.12432814 12.0109791 ISG15 7.11977116 8.56807012 5.30742853 9.49920809 SPON2 2.23572706 8.06242397 3.93168306 3.03210084 ZNF175 7.54187101 7.81634371 7.14944229 7.41388175 RELA 9.42177031 9.20847824 8.87408995 9.18705509 ILF3 11.9717519 11.9811106 12.6029772 11.2341947 CD207 0 0 3.57410151 0 PYCARD 0 6.48816149 0 8.50406418 IL33 0 1.79493566 0 3.46727948 FADD 6.98913901 7.9227925 7.05245937 8.06732679 TRIM5 9.86046626 9.39705422 7.45557381 8.07505123 POLR3F 8.68814538 9.06638524 8.72471848 7.80535695 POLR3E 9.72956976 9.40494994 10.2055 9.47901224 IFIT5 9.48844271 10.1410598 8.86114896 7.2465981 IFNA2 #N/A #N/A #N/A #N/A CD40 0 5.46434153 3.35473424 7.08799315 CXCL9 0 0 0 0 FCN3 1.51096192 1.15704371 0.87970577 0 IFNA8 #N/A #N/A #N/A #N/A IFNA1 0 1.79493566 0 0 IFNL3 #N/A #N/A #N/A #N/A IFNL4 #N/A #N/A #N/A #N/A TRIM11 8.79135827 8.68502907 8.9173124 8.96448527 ABCC9 3.80426012 8.6411486 3.76447355 0 APOBEC3A #N/A #N/A #N/A #N/A APOBEC3H #N/A #N/A #N/A #N/A UNC13D 2.90496572 1.79493566 3.09592442 7.13298804 IFIT1B #N/A #N/A #N/A #N/A IRF9 3.80426012 2.56803211 3.09592442 4.7473874 KCNJ8 0 8.35640795 8.41290852 1.95233357 IFNE 2.49313492 5.24754781 0 0 IFNL2 #N/A #N/A #N/A #N/A PRF1 1.51096192 0 1.422233 3.26603689 IFNL1 0.94860085 0 0 1.95233357 NLRP3 1.91838623 1.15704371 1.422233 11.0042837 LYST 9.96181141 10.1981995 8.7753469 13.2504332 IL6 9.68317008 5.88141991 0.87970577 4.07038933 TRIM25 8.64205169 9.73011345 9.43548275 8.2349611 STAT1 10.5323657 11.6290378 9.89179889 10.8822074 TICAM1 6.50604967 6.29792505 5.14567746 7.05723364 ADARB1 7.52747701 8.00129559 8.32880954 11.6020725 CARD9 5.14118753 7.95901662 5.60969587 9.41970742 SLFN11 0 9.77952239 11.6034038 7.64896869 CRCP 9.8431045 9.64380209 8.78907713 9.83497662 MICA 9.94969542 10.0716769 7.48968743 8.13524755 FAM111A 9.71692232 11.4118605 5.17951105 9.03729985 APOBEC3C 8.5052558 9.04636009 8.08316017 7.10318288 TLR7 0 0 0 2.40871186 BNIP3 8.52352275 9.58942644 9.12887076 9.28331991 DNAJC3 11.2267915 11.9305119 10.2726065 12.6606444 NLRC5 8.91004304 8.71073757 5.45252955 9.89716478 RNASEL 7.02036885 7.61331064 7.04330075 9.09148828 DEFA1 #N/A #N/A #N/A #N/A APOBEC3D 0 1.15704371 5.17951105 2.40871186 POLR3G 7.02036885 7.67553369 9.33784487 6.42240122 GBP3 9.24797497 10.3693356 1.422233 7.8509994 DEFA1B #N/A #N/A #N/A #N/A CXADR 8.76394266 3.86393845 10.2618011 8.50973542 APOBEC3B 5.64731451 6.69125498 6.05419729 3.03210084 DDX41 9.29980329 9.48904513 9.31901723 10.4277214 DEFA3 0 0 0 2.40871186 IFNA5 #N/A #N/A #N/A #N/A POLR3H 9.5733821 9.62590971 9.89689242 9.1103528 POLR3D 10.2445779 9.76324557 9.66008506 10.4216862 DDIT4 8.06058786 5.9692426 8.54194843 9.19768359 IRF5 3.22342255 1.79493566 2.94673086 9.69446236 AZU1 0 0 0.87970577 9.92088874 IL10RB 8.7822775 8.30108459 6.84699469 10.8678579 F2RL1 8.15269046 4.68144927 8.92976142 2.7548875 ABCF3 10.2837135 9.85446325 8.63926835 9.38603491 POLR3C 9.29342567 9.05305702 9.04884103 10.6503876 POLR3B 8.87061131 9.23232498 9.75139342 7.51932174 PLSCR1 8.98056804 8.49105138 8.32503556 9.00537192 CD86 0 0 0 3.03210084 UNC93B1 8.27858884 7.73518367 6.97750891 10.2535875 POLR3A 9.46593366 9.92018907 10.7749435 9.47609811 TRIM56 9.11444511 8.95968323 7.41362793 9.19414124 BCL2 7.951343 6.10454634 7.7977912 10.1893675 ATG7 9.17582397 9.22937162 8.64835758 11.3929184 SAMHD1 9.32086823 9.28745844 10.3386027 11.3193955 IFI44L 3.36036428 4.68144927 1.422233 3.80012335 DMBT1 2.49313492 0 0.87970577 1.28688115 BNIP3L 10.3851829 11.0767822 9.83858941 11.4782185 EXOSC4 7.26594316 8.06910063 8.70165301 9.91230556 GPAM 9.79122802 9.13126536 10.1501154 8.42181238 GBP1 10.7498359 9.71748794 1.422233 6.74577515 CD8A 0 0 0.87970577 3.26603689 IFNA6 #N/A #N/A #N/A #N/A APOBEC1 0 0 0 0 IFI16 10.2555597 10.2117667 3.46858332 10.7184044 BECN1 9.71532713 9.61233407 9.13532452 10.0882582 IFNA21 #N/A #N/A #N/A #N/A IFNA16 0 0 0 0 POLR3K 8.07553263 8.27262979 9.07151599 7.71945728 IFNA10 0 0 0 1.28688115 IFNA14 0 0 0 1.95233357 AIMP1 9.88612332 10.1860399 9.74857864 9.68943895 OPRK1 0 1.15704371 4.56437817 0 TRIM34 2.23572706 2.83995959 0 1.95233357 IRF1 9.12884499 6.9140861 6.71493235 9.41970742 PTPRC 0.94860085 3.4409522 0.87970577 11.4614129 EXOSC5 8.78528898 7.24241196 8.77257851 8.08273452 PMAIP1 10.3239104 9.67459836 10.3534887 9.15104192 BCL2L11 6.52073653 4.53543092 9.14391886 7.90388185 BAD 8.51625158 8.31233844 7.61845892 8.24863919 MAPK14 10.6551819 10.7552298 10.3235727 11.0163417 PENK 0 4.37364821 2.12432814 1.95233357 IKBKE 7.49817107 7.49008872 4.96393645 10.103419 MAPK11 5.82273015 7.48018432 5.65849714 6.99356115 GLI2 6.71149491 8.28406063 7.42071818 2.7548875 LGALS9 0.94860085 2.23266076 2.94673086 9.77945673 PSMB9 6.31777437 4.53543092 4.66277517 8.69620252 ANKRD17 10.669204 11.5978151 11.7991966 11.0183393 PUM1 10.9664406 10.7187469 11.0678108 10.4924541 TRIM15 0 0 1.422233 1.95233357 PUM2 9.37623394 10.8166797 10.5767772 10.219229

TABLE 2 Gene expression of cell surface genes, Related to FIG. 12C. Values represent log2(RPKM + 1). Associated Control: Control: Control: Control: Gene Name CHME_C2 BJ_C3 293_C2 THP_C2 SERPINA5 0 0 4.2 0 GSR 816.46 1060.37 2044.87 3828.89 IGHG1 0 2.47 0.84 0 ITGAX 2.78 0 3.36 4126.29 FCER2 0 0 0 40.23 CD80 0.93 0 2.52 2.87 GPC4 3.71 56.72 225.72 2104.81 CXCL12 864.65 1631.24 31.89 5.75 THY1 1889.63 5680.35 5.03 0 EPOR 48.19 51.79 55.38 67.53 FCGR3A 0 0 0 14.37 LAMP1 4984.96 6167.38 2294.92 5380.56 P4HB 6100.76 8571.7 2824.39 7545.71 CD36 15.75 56.72 5.87 17426.1 IGHA1 1.85 0 0 4.31 MCAM 3140.74 337.84 564.71 31.61 HFE 236.32 265.09 1.68 2.87 TNF 2.78 1.23 0 1432.42 IGHD #N/A #N/A #N/A #N/A TNFRSF13B 0 0 0 0 ITGA3 7291.62 5418.96 125.86 474.12 IL13 0 0 0 2.87 CTSV 34.29 9.86 543.73 87.64 SELL 0.93 0 3.36 0 HEG1 5699.48 4219.27 437.17 1077.55 ALCAM 13497.1 8786.24 1165.5 20703.29 CD5 0 1.23 1.68 4.31 CD40 0 43.15 9.23 135.05 CCR7 0.93 4.93 0 1.44 ECE1 3806.14 3458.52 854.2 715.49 CXCL10 0 0 1.68 22.99 PDPN 35.22 13.56 573.1 231.31 CXCL9 0 0 0 0 IL12RB2 0 7.4 18.46 45.98 ANPEP 529.17 8394.15 2.52 13962.15 SCUBE1 6.49 0 33.56 28.73 CDH13 2046.25 578.27 1.68 0 KCNJ5 0 0 0 94.82 ITGA2B 1.85 2.47 75.52 2.87 SPN 0.93 0 0 931 ITGAE 316.95 422.91 301.23 360.62 CHRNB2 12.05 7.4 20.98 44.54 IGHE 0 0 0 1.44 LILRB1 0 0 0 33.04 GYPA #N/A #N/A #N/A #N/A IGHG4 0 0 0 1.44 CLCN3 919.33 1679.32 3204.5 1193.92 MUC17 0 0 1.68 14.37 SLAMF1 0 0 0 1.44 SCNN1G 0 0 0 0 NGFR 0.93 0 21.82 14.37 CD74 6.49 3.7 10.91 502.86 IGHV3-23 #N/A #N/A #N/A #N/A B4GALT1 2853.45 2168.82 321.37 1647.93 ANTXR2 830.36 2404.32 301.23 3245.57 ENPEP 2.78 17.26 104.05 0 RTN4RL1 21.32 6.16 21.82 15.8 IL2RG 0 1.23 0.84 1.44 CCR1 0 0 0 530.15 BCAM 45.41 73.98 75.52 24.42 CD83 155.69 59.18 151.04 4025.72 TRDC 0 0 0 35.92 CALR 14371.95 13169.49 4740.88 15456.35 CD27 0 1.23 0 0 P2RY12 0.93 0 4.2 2.87 EPHA5 1241.84 38.22 65.45 1.44 TAS2R16 0 0 0 2.87 CTLA4 0 0 0 1.44 HLA-DRB1 0 0 63.77 327.57 SLC22A11 0.93 0 1.68 5.75 FASLG #N/A #N/A #N/A #N/A ASTN1 0 0 5.03 1.44 KCNJ3 0 51.79 17.62 0 CD4 12.97 11.1 15.1 252.86 CLPTM1 1431.82 1474.65 916.29 1261.45 FGA #N/A #N/A #N/A #N/A TLR4 163.11 876.65 0 1084.73 LDLR 2811.74 1258.88 432.97 867.79 ITGA1 632.97 976.52 229.07 218.38 ACE 1.85 12.33 19.3 31.61 IL6 821.1 57.95 0.84 15.8 TNFRSF18 9.27 0 1.68 0 ICOS #N/A #N/A #N/A #N/A TNFRSF14 1.85 66.58 0.84 294.53 IL6ST 10855.88 14455.49 1390.38 1790.17 KLRK1 0 0 6.71 0 CD14 146.43 4.93 2.52 1107.72 CD69 0 0 0 7.18 ANXA5 11189.51 14809.36 2561.75 22499.2 S1PR1 66.73 1740.97 52.02 4.31 MS4A2 0 0 0 1.44 KLRD1 0 3.7 0.84 0 CXCR3 0 0 2.52 4.31 TGFBR3 50.97 573.34 719.1 61.78 SPA17 88.97 108.5 84.75 117.81 TFR2 9.27 9.86 5.03 11.49 CD40LG 0 0 0.84 0 RTN4RL2 3.71 0 22.66 56.03 PECAM1 #N/A #N/A #N/A #N/A CDH5 1.85 0 4.2 2.87 CXCR5 0 0 0 35.92 IGHV3OR16-9 #N/A #N/A #N/A #N/A AMOT 172.37 45.62 6269.7 33.04 TNFRSF11A 309.53 3.7 142.65 337.63 DNAI2 0 0 0 0 CD3E 1.85 2.47 0.84 1.44 ABCG1 0 0 40.28 5.75 IL2RA 0 0 0.84 0 CD226 6.49 19.73 2.52 498.55 CD9 764.56 1099.82 422.06 5101.83 AQP4 0.93 0 21.82 10.06 TNFRSF9 357.72 1.23 9.23 57.47 CD79A 0 1.23 0 0 IGHG2 #N/A #N/A #N/A #N/A ATP6AP2 2344.66 2721.19 1200.74 8345.97 CD48 0 0 0 10.06 GFRA3 9.27 0 3.36 1.44 ENG 6.49 876.65 10.91 640.78 MFGE8 663.55 4594.09 380.11 127.87 SCNN1B 0.93 0 0.84 4.31 ADA 30.58 77.68 168.66 100.57 CHRNA4 0 3.7 5.87 11.49 VCAM1 1071.32 0 0 10.06 GPIHBP1 0 2.47 0 8.62 ICAM1 3634.69 184.95 7.55 4853.28 NLGN1 65.8 242.9 117.47 7.18 CD8B 0 0 0 1.44 FCER1A 0 0 0 0 CCR5 0.93 0 0 5.75 SEMA7A 812.75 2812.43 44.47 4060.2 IL2RB 3.71 3.7 2.52 0 IL1RL1 1.85 0 0 2.87 SLC2A4 1.85 1.23 46.15 5.75 CD79B 0 2.47 3.36 8.62 ADGRE1 #N/A #N/A #N/A #N/A ITGB1 27850.52 46725.12 2770.69 17013.76 TFRC 19994.51 11254.67 4138.41 10202.22 TNFRSF13C 3.71 0 5.03 1.44 THBS1 65649.63 171900.02 12.59 2146.48 CD28 2.78 1.23 0 0 CD24 #N/A #N/A #N/A #N/A CD86 0 0 0 7.18 ENOX2 500.44 304.55 357.45 373.55 IGLL5 #N/A #N/A #N/A #N/A TMEM123 3243.6 4732.19 2818.51 4554.44 CD276 1343.78 1525.2 1057.26 5818.76 PLET1 #N/A #N/A #N/A #N/A TGFBR2 716.37 2530.08 124.19 755.72 SELP 0 1.23 0 0 ITGA5 10868.86 8666.64 369.2 16439.07 IGLL1 0 0 0 0 NRCAM 7.41 14.8 221.52 373.55 IL31RA 8.34 1.23 0 10.06 TRPV1 2.78 3.7 5.03 2.87 FAS 96.38 1336.55 23.49 8.62 IL4 0.93 0 0 0 FCRL6 0.93 0 0 133.62 ITGA6 1820.13 9981 654.49 5346.07 CD19 0 0 19.3 10.06 CTSB 5729.13 19545.25 794.62 64134.21 NRG1 818.32 1087.49 14.26 3090.41 CD274 265.98 1018.44 5.03 41.67 GLRA1 2.78 1.23 5.03 2.87 C10orf54 349.38 288.52 23.49 360.62 CD244 0.93 1.23 0 277.29 FGB 0 0 0.84 0 LAG3 7.41 1.23 5.03 0 CD8A 0 0 0.84 8.62 ITGB6 2.78 4.93 0.84 0 FGG 0.93 0 0 0 IL17A 0.93 0 0.84 1.44 FGF8 0.93 0 0 2.87 CD2 0 0 0 0 IFNG #N/A #N/A #N/A #N/A B2M 18119.7 13594.87 2312.54 52831.45 P2RX7 31.51 6.16 3.36 310.33 CD33 1.85 0 1.68 402.28 IL12RB1 0 0 1.68 53.16 FCER1G 21.32 3.7 0.84 6139.15 TRPM8 9.27 2.47 0.84 162.35 NCAM1 1.85 28.36 417.87 3583.21 ABCA1 993.47 1371.08 20.14 1673.79 ITGA2 312.31 8622.25 213.97 1741.32 CCR4 #N/A #N/A #N/A #N/A ADGRA3 #N/A #N/A #N/A #N/A PLPPR4 #N/A #N/A #N/A #N/A TMC1 0 6.16 0 25.86 CD34 2.78 8.63 1.68 1.44 MS4A1 0 0 0 5.75 ITGAV 8557.56 7863.97 1924.88 7252.62 UMODL1 2.78 1.23 0.84 1.44 PDCD1 0 1.23 1.68 0 BMPR1A 1376.22 1195.99 811.4 313.21 VTCN1 0 0 2.52 0 STAB2 3.71 2.47 2.52 2.87 KIT 15.75 156.59 259.28 8.62 PTPRC 0.93 9.86 0.84 2818.87 IL7R 684.86 2346.37 0.84 1284.44 SDC1 2092.59 2477.06 166.14 96.26 DEFB125 #N/A #N/A #N/A #N/A INTU 343.82 263.86 658.69 71.84 DEFB126 #N/A #N/A #N/A #N/A DEFB127 0 0 0 4.31 HLA-E 2625.47 2870.38 560.51 17693.34 TMX3 4077.67 4949.19 933.91 2418.02 HLA-DPB1 0.93 27.13 77.2 1.44 GP6 0 0 0.84 5.75 CLSTN1 2759.84 2068.95 1345.07 649.4 ADAMTS15 126.04 103.57 80.55 433.89 DEFB128 0 0 0 2.87 DEFB129 #N/A #N/A #N/A #N/A TREML1 0 0 0 60.34 PVR 2796.91 3094.79 539.54 1030.14 PLAU 2690.34 1626.3 18.46 10226.65 PSEN1 1368.8 1232.98 963.28 2409.4 DEFB110 0 0 0 0 FAP 499.52 3030.67 0 166.66 HLA-B 8261.92 2716.26 1006.91 11506.77 DEFB112 #N/A #N/A #N/A #N/A PVRL2 1138.97 1057.9 453.95 1657.99 ENPP1 1018.49 1452.45 882.73 10.06 HNRNPM 3212.1 2785.31 3958 1596.21 TMEM102 21.32 36.99 64.61 186.77 ITGA8 0 110.97 198.03 2.87 PLA2R1 110.28 400.72 15.94 1.44 TIMP2 1309.49 6331.37 232.43 372.11 LRFN2 0 0 1.68 22.99 EPPIN 0 0 0 1.44 DEFB132 #N/A #N/A #N/A #N/A ITGA7 215 157.82 162.78 295.97 PLXNB2 1633.85 3714.98 542.89 4109.05 BMPR2 1161.21 3140.41 1145.36 768.65 CD1B 0 1.23 0 2.87 EPHA4 485.61 1341.49 667.92 0 K1SS1R 1.85 0 4.2 7.18 CPM 86.19 110.97 67.13 366.37 HPN 2.78 0 0.84 0 ADAM8 25.02 38.22 28.53 110.63 SHH 0.93 0 5.03 10.06 SLC46A2 1.85 0 1.68 1.44 EPPIN- #N/A #N/A #N/A #N/A WFDC6 RSPO2 0 2.47 6.71 5.75 HFE2 0 0 1.68 0 NT5E 5570.66 10477.89 10.91 11357.35 SLC6A3 0 0 1.68 10.06 AOC3 6.49 1.23 26.01 0 EPHB6 2.78 17.26 57.9 10.06 FZD1 227.05 632.52 235.79 476.99 BACE2 3244.53 634.99 338.99 10.06 PLAT 587.56 2657.08 380.11 12.93 VAMP7 #N/A #N/A #N/A #N/A ADAMTS9 56.53 22.19 166.14 4.31 AAMP 1613.46 1400.67 1829.22 1719.77 SRPX2 67.65 415.52 6.71 311.77 NOTCH4 23.17 16.03 19.3 43.1 AREG 0 1.23 0.84 234.19 IL1R1 1002.74 1033.24 27.69 2274.34 TNFRSF10B 1149.16 2384.59 961.6 1678.1 MMP7 0 2.47 0 66.09 HLA-C 1488.35 3525.1 2200.1 1759.99 AQP11 10.19 29.59 39.44 33.04 IL1RAPL1 0 7.4 1.68 0 ITGB3 252.07 182.48 2.52 1395.07 DCBLD2 18375.48 12247.22 1267.03 1182.43 TSPAN14 582.92 1001.18 314.66 1145.07 TLN1 13822.39 15083.08 2081.79 24480.45 BACE1 944.35 1437.66 319.69 370.68 PAM 3327.94 10582.69 1517.08 6860.39 TGFB1 420.74 522.78 105.73 1495.64 CNTN2 6.49 3.7 5.87 0 LRFN5 0 1.23 63.77 38.79 HYAL4 0 0 0 0 NEU1 1231.64 757.05 871.82 6440.86 ANXA1 10183.07 19419.48 353.26 1718.33 NOD2 0 1.23 16.78 1.44 TEK 2.78 165.22 5.87 0 ADAM15 1040.73 1115.85 587.37 1188.18 SULF1 1404.94 14641.67 57.06 1.44 ROS1 40.78 16.03 0 1.44 ADGRG2 #N/A #N/A #N/A #N/A C1QBP 3661.57 2906.14 7797.69 2988.4 DEFB116 #N/A #N/A #N/A #N/A FGFR3 70.43 32.06 360.81 11.49 SORT1 442.06 1918.52 1380.31 403.72 PRLR 12.97 102.34 2.52 126.43 FZD4 25.95 655.95 287.81 45.98 SDC3 113.99 638.69 176.21 360.62 CCR6 #N/A #N/A #N/A #N/A TSPAN15 186.28 11.1 238.3 127.87 RER1 2869.2 2903.67 1359.33 2476.92 HLA-DMA 12.05 18.49 15.94 12.93 CTSG 0.93 0 0 260.05 DEFB115 0 0 0 0 ISLR2 6.49 1.23 2.52 5.75 VAMP4 283.58 307.01 196.35 283.04 GRIN2A 124.18 0 2.52 0 VLDLR 438.35 340.3 93.14 553.14 TRPV2 0.93 387.16 27.69 3130.64 HLA-A 3051.77 1927.15 487.51 8402 KCNK2 151.06 940.77 8.39 0 FZD6 963.81 1036.94 445.56 905.14 ADGRA2 #N/A #N/A #N/A #N/A ENTPD2 0.93 0 0.84 1.44 CAV1 7135.93 14644.14 137.61 1567.47 ACVR2A 243.73 194.81 224.88 1089.04 EPCAM 0 9.86 29.37 2.87 PROM2 6.49 1.23 9.23 7.18 DPP6 0.93 1.23 0 10.06 TGFA 2.78 429.08 6.71 30.17 RAMP3 #N/A #N/A #N/A #N/A HILPDA 202.03 152.89 255.08 100.57 ANGPTL3 3.71 7.4 20.14 4.31 FZD5 84.33 44.39 378.43 191.09 ITGAM 5.56 0 1.68 2543.01 AGER 25.02 4.93 11.75 30.17 SFRP4 3.71 14.8 5.87 0 FZD9 60.24 16.03 94.82 110.63 AXL 8602.97 12761.37 11.75 77.58 TNFRSF4 0.93 1.23 0 15.8 APOH #N/A #N/A #N/A #N/A PDGFB 42.63 1.23 4.2 102.01 SCUBE3 26.88 636.22 88.1 30.17 RAMP1 174.23 23.43 0 459.75 DEFB131 0 0 1.68 0 ATPIF1 1312.27 890.21 1329.96 476.99 HLA-F 119.55 48.09 94.82 0 USP14 463.37 1421.63 1088.3 364.93 VEGFA 494.88 389.62 264.31 2316.01 IGSF5 0 0 0.84 0 BGN 0.93 960.49 0 0 NDP 4.63 1.23 2.52 0 HSP90AA1 19879.59 19462.64 25695.55 17723.51 PLVAP 0 0 0 50.29 PDGFA 152.91 202.21 37.76 8097.41 PDGFC 1682.04 2290.88 476.6 459.75 PKD1 1806.22 1681.79 453.95 1114.9 ABCA7 28.73 41.92 160.27 58.91 CASR 0 0 0.84 8.62 CA4 0 0 0.84 2.87 WNT6 0.93 0 5.03 12.93 LAYN 896.16 2523.92 208.93 11.49 DSCAML1 0 0 0.84 11.49 AMELX 0.93 0 0 1.44 RTP1 #N/A #N/A #N/A #N/A SFRP1 57.46 5580.48 860.07 11.49 CAPN5 125.11 204.68 69.64 8.62 ITGB4 9.27 3.7 12.59 7.18 BMP2 2.78 16.03 372.56 304.59 PHB2 2374.32 2266.22 4521.03 1254.27 RC3H2 3561.48 2580.63 2155.63 1518.62 TFPI 1318.76 1229.28 125.86 117.81 LILRB2 0 1.23 1.68 5.75 EGFR 1550.44 4208.17 265.99 24.42 IL17RC 226.13 297.15 82.23 209.76 TPBG 1430.89 3515.23 312.14 195.4 IGF2R 5385.31 6237.66 2798.38 10809.96 CAV3 2.78 6.16 3.36 1.44 PPFIA4 14.83 22.19 86.43 155.17 P2RY1 0 1.23 197.19 25.86 NOTCH2 7605.79 7362.14 5396.21 4916.49 CLSTN2 11.12 112.2 29.37 583.31 MICB 339.19 537.58 198.03 431.02 F3 9729.89 5384.44 41.12 349.13 NRDC #N/A #N/A #N/A #N/A KCNN2 0 91.24 8.39 91.95 HLA-DRA 0 0 5.03 2.87 HLA-DPA1 2.78 36.99 73 11.49 LPAR2 11.12 0 35.24 102.01 RTP5 #N/A #N/A #N/A #N/A MPL 1.85 0 0.84 21.55 VASN 1258.52 1649.73 43.63 33.04 CD109 569.95 3114.51 352.42 11847.28 TNFRSF10A 44.48 88.77 99.01 443.95 WNT4 22.24 7.4 14.26 8.62 ADAM10 4097.14 3844.44 1270.39 4950.97 ACHE 1.85 4.93 13.43 11.49 STX4 392.94 484.56 281.94 1517.19 FOLR2 0 0 0 4.31 VAMP1 50.97 29.59 88.1 28.73 CST8 0 0 0.84 0 GOT2 2876.61 2511.59 3760.82 685.32 NLGN4X 0 20.96 0.84 1.44 ROBO1 2049.96 1352.58 3197.78 268.67 NLGN2 240.03 224.4 261.8 22.99 TSPAN32 1.85 7.4 1.68 5.75 FLT3LG 0.93 0 1.68 2.87 RALA 1279.83 2124.43 521.92 543.08 DEFB118 0 0 0 0 NOTCH1 428.16 660.88 272.71 3455.34 TSPEAR 0 0 0.84 1.44 CLEC2D 19.46 34.52 62.09 97.7 ACVR1B 236.32 341.54 470.73 403.72 PRNP 3003.58 8878.71 387.66 435.33 PCSK6 0.93 6.16 573.1 2370.61 MET 4298.24 9022.97 1319.89 5883.41 TNS1 242.81 1433.96 68.81 685.32 CD38 0.93 0 0 21.55 GPRC5B 336.41 9.86 213.13 0 CLEC9A 0 0 0 0 PROM1 0 0 2.52 1.44 APP 7446.39 12740.41 3200.3 2630.65 EPHA2 1506.89 2158.95 250.89 64.65 IL17RB 38 59.18 133.42 18.68 DEFB104B #N/A #N/A #N/A #N/A CX3CL1 6.49 1.23 0 1.44 TNFRSF1A 1099.12 1051.73 253.41 929.56 KCNE1 3.71 7.4 1.68 27.3 NLGN4Y 1.85 340.3 0 18.68 F2R 2846.96 670.74 422.9 130.74 MST1R 6.49 2.47 18.46 2.87 FGFR2 1019.42 0 612.54 0 SLITRK6 0 34.52 5.87 0 LRPAP1 925.82 2080.04 2327.64 2285.84 CNTNAP2 15.75 0 391.02 7.18 ANO6 2874.76 3986.23 1102.57 5188.03 KCNH1 29.66 64.12 0.84 0 CXCR4 3.71 0 305.43 360.62 TNFSF18 0 17.26 0 211.2 CD59 11243.26 17745.09 1050.54 4234.04 WNT1 0 0 0 1.44 SCARB1 99.16 397.02 535.34 479.87 TGFB3 84.33 32.06 73 905.14 RTP2 0 0 0 0 APOA1 0 0 0 5.75 42615 9398.11 11122.74 5421.38 4913.62 DEFB108B 0 0 0.84 0 SLC7A11 1925.77 3377.14 1023.69 10483.82 ACKR3 63.95 16.03 0 231.31 CCR2 0 0 0 0 SULF2 128.82 207.14 307.11 241.37 ELANE 0.93 0 0.84 318.95 NFAM1 1.85 0 2.52 91.95 ERP44 926.74 893.91 568.07 1061.74 GJD3 0 2.47 0 1.44 DMD 360.5 103.57 394.37 5.75 HSP90AB1 17579.41 17217.37 26755.32 31876.74 TNFSF4 12.05 98.64 9.23 34.48 MRC1 0 0 0.84 2.87 ROBO2 0 25.89 273.54 0 DEFB123 #N/A #N/A #N/A #N/A IL15 56.53 66.58 9.23 5.75 GRIN2B 1.85 0 10.91 1.44 LPAR1 316.95 3804.99 110.76 214.07 KCNQ3 1.85 27.13 0.84 97.7 MOG 0 0 0 1.44 ADCYAP1R1 0 4.93 129.22 0 ULBP2 187.2 187.41 40.28 451.13 ANXA9 26.88 23.43 52.02 63.22 LRFN1 1.85 1.23 117.47 14.37 GRIA1 9.27 32.06 0.84 1.44 TIGIT 3.71 2.47 0.84 15.8 HAVCR2 7.41 1.23 1.68 6175.07 BMP10 0 0 0 15.8 WNT7A 0 0 0.84 2.87 ITGB8 366.06 25.89 53.7 1303.11 SERPINF2 0 0 0 2.87 MICA 987.91 1075.16 178.73 280.16 C5AR1 9.27 3.7 7.55 6800.05 SLC9A1 239.1 447.57 177.89 297.4 SLC1A4 781.25 660.88 204.74 2344.74 BST2 0 2.47 5.03 1475.52 DPP4 56.53 1257.64 45.31 37.35 DEFB124 0 0 0 0 AMBP 0 1.23 1.68 0 TACR1 3.71 8.63 11.75 10.06 MBL2 0 1.23 0 0 SLC1A2 19.46 122.07 17.62 7.18 CLU 106.58 220.7 849.16 7.18 KCNA1 0 2.47 37.76 0 NRP1 5861.66 7359.68 1056.42 9143.35 ADGRF5 #N/A #N/A #N/A #N/A SLC34A1 1.85 2.47 0 1.44 KCNH2 0.93 2.47 83.07 21.55 SLIT2 506.93 4476.96 5873.65 11.49 HSPA2 351.24 1006.11 277.74 11.49 ANXA2 25181.49 34633.26 1884.6 11707.92 CSF1R 28.73 9.86 2.52 6659.25 ATP5B 9864.27 8677.73 9815.71 9950.8 LGALS1 15675.88 18436.79 36.92 14558.39 SDC4 2178.78 3317.96 232.43 1274.38 TREML2 0 0 0.84 2.87 SLC1A3 305.83 1.23 777.84 6633.38 LRP4 85.26 161.52 340.67 5.75 HMMR 2825.64 1721.24 1414.71 41.67 TPO 0 0 2.52 0 FUT4 74.14 139.33 158.59 412.34 NTRK1 0 1.23 4.2 30.17 HCST 2.78 6.16 1.68 228.44 PPFIA3 49.12 33.29 271.87 364.93 ENTPD6 557.9 865.55 631.84 1581.84 ITGA4 840.56 2779.14 101.53 1390.76 ABCB1 1.85 6.16 335.64 767.21 SLC46A1 8.34 127 163.62 10.06 CORIN 8.34 67.81 47.83 15.8 PTN 227.98 356.33 0.84 0 LBP 0 3.7 0.84 8.62 VAMP5 31.51 170.15 2.52 5.75 KCNH5 0 0 0 1.44 RARA 66.73 196.04 164.46 294.53 GHR 4.63 53.02 125.02 17.24 WNT5A 3125.91 9417.52 673.79 11.49 KRT4 0 0 2.52 1.44 CD93 0.93 1.23 1.68 4.31 PLA2G1B 0 0 0 0 MIF 3.71 0 3.36 2.87 LPL 16.68 4.93 57.9 8696.53 RGMA 0.93 6.16 135.09 35.92 FURIN 1091.7 1736.04 648.62 3894.98 WNT3A 0.93 0 5.03 5.75 NRXN1 0 3.7 39.44 2.87 CXADR 433.72 13.56 1226.75 363.49 OTOA 0 3.7 0 35.92 CCR10 1.85 7.4 8.39 0 FOLR1 0 7.4 5.03 4.31 HNRNPU 13535.1 10796 18000.22 7328.76 TRPV4 11.12 73.98 43.63 0 DSG2 2194.53 3.7 2941.86 8.62 HMGB1 3941.44 3274.8 3229.67 1441.04 DEFB105A #N/A #N/A #N/A #N/A TNN 0 0 0 21.55 CEP41 640.38 356.33 229.91 168.1 DEFB106A #N/A #N/A #N/A #N/A SLC39A6 3077.72 3096.02 2691.81 1745.63 DEFB119 #N/A #N/A #N/A #N/A CYP2W1 12.05 0 1.68 12.93 ITGAD 0 0 0 11.49 ERP29 1138.04 1210.79 1036.28 1169.5 NCL 6730.94 9053.79 12308.66 4459.61 MSLNL 2.78 0 0 11.49 CHRNA1 0 0 0 0 HM13 925.82 1623.84 844.13 2709.67 GPRC6A 0 0 2.52 1.44 FSHR 0 0 0 1.44 CFTR 0 0 0 0 SCARA5 3.71 0 12.59 2.87 HTR3B 0 0 1.68 0 PDIA4 7894.01 4655.74 4646.06 5713.88 DEFB121 #N/A #N/A #N/A #N/A IDE 1798.81 1387.11 2008.79 999.96 CD55 1032.39 578.27 435.49 601.99 SLC11A2 668.18 774.31 789.59 1249.96 ART1 0 0 1.68 5.75 CD63 4658.74 12189.27 1426.46 27445.86 LTF 0.93 1.23 0 0 SDC2 2325.2 1292.17 849.16 25055.14 DEFB135 0 0 0.84 0 CLDND1 1820.13 674.44 601.63 1120.65 HYAL2 353.09 536.35 263.48 478.43 PLG #N/A #N/A #N/A #N/A ABCC2 12.05 7.4 31.89 4.31 GPA33 0 0 0.84 0 FERMT2 3622.64 4988.65 1468.41 2136.42 CDON 109.36 51.79 612.54 178.15 DEFB104A #N/A #N/A #N/A #N/A NTSR1 1.85 1.23 2.52 446.82 SLC3A2 4065.63 2416.65 2212.69 4867.64 DEFB134 0 0 4.2 0 KCNE2 0 2.47 3.36 0 PTPRK 2879.39 3060.26 839.93 854.85 CR1 0 0 0.84 0 TMEM206 345.68 208.37 260.12 636.47 CLMP 1010.15 4830.83 44.47 701.12 BSPH1 0 1.23 0 0 CCR9 0 2.47 3.36 2.87 DIP2A 598.68 622.66 620.09 619.23 SLC12A1 0.93 0 0 1.44 ALPP 2.78 0 0 1.44 TRPC4 226.13 482.1 4.2 0 CLSTN3 141.79 125.76 407.8 43.1 NLGN3 0 0 10.91 10.06 SLC9A3 38 14.8 18.46 109.19 PKD1L3 9.27 1.23 6.71 5.75 TLR2 67.65 1.23 0 4869.08 LMAN2 2015.67 1701.52 1616.93 3905.03 CXCR2 0 2.47 0 1.44 UNC5D 0.93 0 5.03 4.31 ARSB 506.93 1330.39 443.04 1126.4 LY9 0 1.23 0 7.18 ADAMTS7 66.73 101.1 20.98 68.96 ADGRV1 #N/A #N/A #N/A #N/A CD58 386.45 106.04 78.04 992.78 RAMP2 0.93 4.93 8.39 0 ITGB7 17.61 11.1 22.66 7410.66 CD209 0 0 1.68 254.3 TF 3.71 4.93 1.68 4.31 CSPG4 1107.46 4628.62 184.6 5452.39 MPZL1 2875.69 4459.7 1355.14 425.27 BSN 3.71 8.63 172.01 54.6 DEFB106B #N/A #N/A #N/A #N/A PCSK9 0.93 4.93 0.84 0 ITGB5 2682.92 4758.08 330.6 11916.24 SYNJ2BP 385.53 495.66 432.97 228.44 STRC 0 1.23 5.03 2.87 HSPA5 9589.95 11079.58 3310.22 8166.38 SLC6A1 0 0 2.52 8.62 LRP6 1013.86 1811.25 1961.8 334.76 IGSF3 635.75 13.56 647.78 22.99 CLEC5A 0 0 2.52 173.84 PPFIA2 1.85 2.47 20.98 70.4 ADAM2 0 0 0 2.87 ADIPOQ 0 0 0 1.44 ANXA4 507.86 940.77 157.75 2067.46 VAMP3 3101.81 3133.01 1464.22 968.36 PTPRT 0 2.47 0 2.87 MAS1 0 0 0 0 PROCR 124.18 237.97 192.99 183.9 RPS6KB1 733.98 880.35 1190.67 800.26 SRPX 345.68 438.94 44.47 30.17 FOLH1 0 0 7.55 0 APOA4 0 0 0 0 SPARC 57829.76 44322.04 1261.16 4.31 PTPRJ 1197.35 432.78 202.22 2231.24 LIPC 0 0 0 1.44 TNR 0 1.23 0.84 7.18 LY6D 0 1.23 0 7.18 ACE2 0 0 38.6 0 CRYAB 4.63 404.42 0 0 PDIA3 5239.81 5045.37 2471.97 5277.11 ITGAL 0.93 0 5.03 337.63 TSPAN33 6.49 1.23 260.12 137.93 HBEGF 655.21 360.03 115.79 6509.83 TDGF1 0 0 0 0 FAM89B 88.97 80.14 34.4 79.02 MFI2 1454.06 48.09 63.77 928.13 CLEC17A 0.93 0 0 8.62 DEFB133 #N/A #N/A #N/A #N/A DEFB105B #N/A #N/A #N/A #N/A APMAP 2555.03 2361.16 1298.92 1343.34 CD44 8078.43 15258.16 31.05 5098.96 SLC26A9 0 0 0 11.49 ADAMTS13 28.73 24.66 72.16 12.93 SPTB 17.61 69.05 255.92 12.93 ANTXR1 1074.1 2781.61 429.62 66.09 WNT5B 1189.01 4162.55 90.62 43.1 GP1BA 4.63 2.47 10.07 1.44 CLIC4 21061.19 23371.19 2396.45 7327.33 TNFRSF12A 4668.01 3546.06 57.9 1764.31 SCN5A 8.34 48.09 125.02 7.18 ACVRL1 0.93 125.76 3.36 202.58 CD46 3627.28 2697.77 885.24 1976.94 PHB 1395.68 1446.29 2807.61 1543.05 LRFN3 80.63 82.61 57.9 132.18 HHIP 63.95 30.82 21.82 4.31 EPO 0.93 1.23 4.2 0 MXRA8 1561.56 3856.77 109.08 37.35 EMP2 602.38 1049.27 454.79 54.6 TYROBP 3.71 4.93 0 4159.33 LIPG 103.8 48.09 40.28 37.35 CD1D 0 0 12.59 281.6 PTGFRN 2385.44 271.26 1443.24 68.96 RTN4R 21.32 13.56 41.95 57.47 GREM1 22408.67 27412.91 5.03 0 HSPD1 7264.75 9067.36 16483.14 6369.03 FGF22 0.93 3.7 4.2 2.87 FZD10 0 0 48.67 4.31 CDH17 0 0 0 5.75 CD53 4.63 0 5.03 10462.27 GHRHR 0 0 1.68 0 FAM234A #N/A #N/A #N/A #N/A DCSTAMP 0 1.23 0 2160.84 NTRK2 0 28.36 29.37 0 GRIN1 3.71 3.7 4.2 15.8 MMP16 1448.5 2273.62 422.9 10.06 FGFBP1 1.85 0 3.36 0 PTGER3 2.78 60.42 0.84 91.95 FZD3 3.71 54.25 1356.81 329.01 ADAM9 6785.62 11556.75 1445.76 23152.91 ADAM17 854.46 641.15 644.42 7614.67 AIMP1 945.28 1163.94 859.23 824.68 NPTN 3350.18 3957.88 1011.95 2890.7 THBD 13.9 12.33 20.98 12960.75 GHSR 0 1.23 0.84 0 PKD2L1 0 0 3.36 4.31 CIITA 12.97 3.7 9.23 5.75 IL6R 46.34 104.8 103.21 10480.95 LRFN4 518.05 425.38 137.61 522.97 L1CAM 315.09 2055.38 9.23 86.2 IQGAP2 15.75 0 873.5 1747.06 LRRC8A 1452.21 1965.37 495.9 1748.5 KCNC1 2.78 3.7 88.1 21.55 MSLN 12.05 3.7 1.68 12.93 TMEM8B 45.41 51.79 53.7 10.06 EGFLAM 2.78 43.15 28.53 4.31 FGF10 0 1.23 1.68 1.44 ANK3 22.24 0 510.17 20.11 ASIC1 34.29 34.52 173.69 7.18 ITGB2 84.33 1.23 9.23 60433.2 FCN1 0 0 0 2.87 SERPINE2 1060.2 15343.24 185.44 5369.06 ARSA 203.88 229.33 80.55 903.7 CUBN 16.68 6.16 15.1 37.35 F10 1.85 203.44 6.71 2.87 GGTLC3 0 0 0.84 0 PKHD1 0 0 4.2 5.75 GGT6 0 0 0.84 4.31 GGTLC1 0 0 0 1.44 GGTLC2 #N/A #N/A #N/A #N/A GGT2 0.93 0 0.84 0 GGT1 5.56 11.1 12.59 99.13 GGT7 83.41 178.78 138.45 53.16 GGT5 0.93 41.92 0 10.06 EFNA5 373.48 9.86 853.36 22.99 SPIRE2 42.63 27.13 135.93 58.91 SVIL 430.94 797.74 400.25 965.48 STAMBP 372.55 461.14 933.91 808.88 MEN1 435.57 329.21 787.07 352 SSH1 696.91 1824.81 440.52 1402.25 RHOB 261.34 2446.24 1559.87 1538.74 ECT2 7855.08 3380.84 1538.06 307.46 NDE1 683.94 409.35 336.48 593.37 RDX 2478.11 3427.69 2886.48 1874.93 WDR73 398.5 356.33 735.05 603.43 RAB11A 2263.11 2643.52 2510.57 1991.31 MYH10 2296.47 3358.65 4572.22 22.99 OR2A4 #N/A #N/A #N/A #N/A RAB21 1267.79 1980.17 1142.84 1695.34 PLCD3 198.32 410.58 365.84 168.1 SPIRE1 877.63 981.45 401.09 1051.69 RAB11FIP3 620.92 815 603.31 376.42 PLEKHG6 12.05 12.33 2.52 5.75 NF2 4767.17 5857.9 1955.93 1782.98 PLK4 707.11 870.49 724.14 40.23 MYH9 25389.08 38543.05 4544.53 18536.7 RHOC 2790.43 2981.35 412.83 8746.82 ARF6 1402.16 1914.82 688.06 2025.79 PDXP 57.46 32.06 62.93 31.61 PKN1 1402.16 1950.58 1598.47 2216.88 RAB11FIP4 12.97 6.16 819.79 1313.17 PKN2 1518.01 1840.84 2245.41 456.88 FSD1 274.32 149.19 430.45 1.44 42619 382.75 392.09 848.32 170.97 MYLK 5096.17 15322.28 196.35 271.54 MASTL 1404.94 872.95 995.16 281.6 PSTPIP1 4.63 3.7 0.84 155.17 LIMA1 4424.28 8031.65 672.11 1073.24 RACGAP1 3694.93 3748.27 1490.23 216.95 DCTN3 970.3 744.72 292 928.13 42625 0 0 4.2 1.44 42620 5790.3 5566.92 1887.96 3558.78 ZFYVE19 187.2 304.55 234.95 308.9 PITPNM1 877.63 360.03 224.04 935.31 CEP55 3899.74 2687.9 1152.91 66.09 PPP1CC 2543.91 3158.9 4695.56 2711.11 RHOA 7032.13 11043.83 4682.14 11876.01 CEACAM5 0 1.23 0 0

TABLE 3 Gene expression of immune response genes, Related to FIG. S2F. Values represent log2(RPKM + 1) Control: Control: Control: Control: gene name CHME_C2 BJ_C3 293_C2 THP_C2 C3 9.1572206 6.75848974 2.94673086 10.4426947 FCER1G 4.48026512 2.23266076 0.87970577 12.5840582 EPHB6 1.91838623 4.19061486 5.88019573 3.46727948 GATA3 1.51096192 2.83995959 6.78240857 2.7548875 IL20RB 4.59514557 3.59693514 4.40190347 4.7473874 SPN 0.94860085 0 0 9.86418615 ZP3 2.49313492 2.23266076 3.76447355 0 FCER1A 0 0 0 0 FCN2 0.94860085 0 0.87970577 0 FCN1 0 0 0 1.95233357 FCN3 1.51096192 1.15704371 0.87970577 0 MASP1 0 10.3061073 2.37851162 0 MBL2 0 1.15704371 0 0 KRT1 1.91838623 0 0.87970577 0 MASP2 4.06608919 3.98185265 5.70542504 3.64270157 A2M 5.14118753 9.20244221 3.35473424 15.3594658 SERPING1 0 7.34447346 3.76447355 0 CTSC 8.74224206 11.7732258 9.34717842 13.1142401 MICB 8.41019692 9.07301685 7.6368421 8.75495429 RAET1E 0 2.56803211 0.87970577 1.95233357 MICA 9.94969542 10.0716769 7.48968743 8.13524755 CTSH 4.35473424 6.32030415 8.17816686 12.0024177 EMP2 9.23692307 10.0365445 8.83222546 5.79701298 RIPK3 0.94860085 4.28466219 0 7.08799315 LILRB1 0 0 0 5.08915913 PPP3CB 9.64859127 9.58248074 9.13962809 9.42273759 PTPRC 0.94860085 3.4409522 0.87970577 11.4614129 IL7R 9.42177031 11.1968296 0.87970577 10.3280466 HLA-E 11.3589094 11.4875286 9.13316791 14.1110003 FADD 6.98913901 7.9227925 7.05245937 8.06732679 HLA-A 11.5759032 10.9130016 8.93224429 13.0366888 IL12A 4.06608919 4.68144927 3.46858332 3.26603689 XCL1 0.94860085 0 3.35473424 0 IL12B 0.94860085 0 0.87970577 1.28688115 STX7 10.7152671 10.2905719 9.93572493 10.1840199 IL23R 0 0 0.87970577 0 HLA-B 13.012436 11.4079369 9.97715111 13.4903207 B2M 14.1453511 13.7308809 11.1758863 15.6891367 P2RX7 5.02281165 2.83995959 2.12432814 8.28230079 IL12RB1 0 0 1.422233 5.75915583 IL23A 2.71369582 1.15704371 2.94673086 3.80012335 C6 0 1.79493566 0 3.03210084 CD59 13.4569011 14.1152136 10.038288 12.0481599 MSH2 10.3405066 10.7060297 11.8397234 9.15830673 MLH1 10.3801688 10.2340869 7.88233736 9.78886512 PYCARD 0 6.48816149 0 8.50406418 TRIM5 9.86046626 9.39705422 7.45557381 8.07505123 TBK1 9.82257083 9.62815387 9.10268437 10.9339783 TMEM173 7.41438927 9.43352285 4.79960542 8.9561438 MB21D1 8.92389197 8.76081973 2.37851162 8.90517638 MAVS 9.78517453 10.0617222 9.2806084 8.62972089 NLRC4 2.49313492 2.56803211 4.00898878 7.35182265 PYDC1 0 0 1.422233 0 TLR4 7.35851934 9.77750191 0 10.0844497 SIN3A 9.49215363 9.52085436 10.3320477 8.94356975 HMGB1 11.9448731 11.6776316 11.6576177 10.4938955 AIM2 0.94860085 1.15704371 0 6.00495076 IFI16 10.2555597 10.2117667 3.46858332 10.7184044 CD36 4.06608919 5.8509994 2.7803101 14.0890449 PGLYRP3 0 0 0 0 PGLYRP4 0 0 0 2.7548875 PGLYRP2 0 1.15704371 0 1.95233357 MARCO 0 0 0.87970577 6.37312616 PGLYRP1 1.91838623 1.15704371 1.81557543 2.7548875 DMBT1 2.49313492 0 0.87970577 1.28688115 TRAF6 8.64871709 8.3400281 8.35124846 9.37046946 PSMB9 6.31777437 4.53543092 4.66277517 8.69620252 PSME3 10.6096959 10.9744146 11.5052062 10.8689691 CARD11 0.94860085 1.15704371 0 1.28688115 ITPR3 9.35801377 10.8245451 7.50311018 6.39797405 FBXW11 11.0875093 10.986738 10.59646 11.8201032 PSMC6 10.6968545 10.6704527 10.2608137 10.8193568 PPP3R1 8.26129574 9.5684882 8.94213326 8.82975444 UBE2M 10.1022251 9.85252951 10.0947375 10.4292184 CHUK 10.3640252 10.2676645 10.3936371 10.298727 RELA 9.42177031 9.20847824 8.87408995 9.18705509 TAB2 10.4304526 10.0109057 10.1522468 11.5744705 NFATC2 5.02281165 4.37364821 5.4799419 3.64270157 PSMB4 12.1831639 11.3914799 11.6341985 13.4676285 PSMA7 11.9091656 11.864782 11.4981062 12.0437485 PSME4 9.96849401 11.4099 11.3813483 10.3134613 PSMB8 8.70106383 7.99429686 0 11.5239833 MAP3K14 7.08087081 6.56544486 6.33467553 8.04395687 UBE2V1 5.38474059 5.24754781 5.58466191 5.86962469 PSMD12 10.8239881 11.1085506 11.6368602 10.5830734 PSMC2 11.8610947 11.2013643 10.670373 11.4948306 SRC 8.6218321 9.06638524 8.17397689 10.5830734 PSMB11 0 0 0 1.95233357 LYN 7.71094416 9.30444259 8.25148241 10.9633441 PSMD1 12.0960595 12.2104735 12.0019887 12.0324143 PSMC5 9.68804045 10.1489087 9.65257612 9.75328362 UBE2D2 10.9469355 10.7324049 10.8311726 10.6581133 PSMD10 10.2190112 10.1644922 10.6509261 9.92301544 UBA52 12.4517881 12.1573375 12.2104765 12.7400485 UBC 13.4396764 13.4964194 12.1089001 13.7277727 PSMB1 11.9810428 11.080078 11.2876085 11.8394636 PRKACB 9.88045595 10.0683752 8.49908847 8.31524015 PSMB3 10.3650429 10.638445 11.2227345 11.5197542 PSMD5 9.88612332 10.5319467 2.12432814 7.73903798 RPS27A 11.6338489 12.3918719 12.0447322 12.2767147 PLCG2 2.71369582 3.2675358 7.21606678 8.61393677 PSMC4 11.1611697 10.7176936 10.4783854 11.3120775 UBE2D1 8.70746267 8.23174919 8.89965903 9.0333404 ITPR2 9.41396635 10.2863036 9.64805193 10.3662348 PSMA5 11.4869356 11.1592091 10.999091 12.5279559 CALM1 12.4099 12.7602542 11.8655825 12.9502843 CLEC7A 0 0 0.87970577 5.20633065 NFKB1 10.0602636 9.95106611 9.21897486 11.0558247 PSMD13 11.5640304 10.986738 10.4673101 11.624567 KRAS 9.58560105 9.90356556 10.2449465 8.9891674 CASP8 7.951343 8.28974227 8.10527998 9.26322225 PPP3CA 8.96993328 10.8953708 9.51042793 9.45557381 PSMD9 8.03529399 7.87817356 7.34082928 7.60703435 PDPK1 9.62338771 9.82338316 9.26692706 9.65644274 NRAS 12.0997193 11.176223 11.5332519 13.2913247 SKP1 11.314453 11.1823571 11.0655508 11.4105415 ITPR1 6.76155123 7.30003218 9.25507579 11.6525224 ICAM2 0 3.07038933 1.81557543 2.7548875 EP300 9.47348253 9.74262944 10.7420989 10.1442886 CARD9 5.14118753 7.95901662 5.60969587 9.41970742 PSMD7 10.7428315 10.2370426 10.0531792 10.2704705 PSMC3 12.3383798 11.622848 11.3263115 12.1474466 PSMD3 10.9870081 11.3278558 11.7714152 11.5225766 KLRK1 0 0 2.94673086 0 PSMB6 11.0298463 10.3103174 10.4664538 11.2444828 TAB3 9.12644637 8.77307325 8.99765936 9.2766595 PSMB10 6.69863522 5.65306002 3.23112516 8.71111629 RPS6KA5 5.84624257 5.24754781 7.45557381 7.33904828 PSMD6 10.9850307 10.9744146 11.0879733 10.6230493 PRKACA 8.85626989 8.85218616 8.57088032 7.78672704 CLEC4D 0 0 0.87970577 0 PSMA2 9.02231232 8.37794796 8.84805952 8.59797804 ICAM3 7.20388631 6.8992965 6.9582627 8.12044526 PAK2 11.6732737 10.9102305 10.1437148 11.3766409 MALT1 10.6944363 10.8008109 9.27865853 10.8353241 PSMD4 11.4625074 10.6682645 11.2914758 12.9257213 SYK 0.94860085 1.79493566 8.44799238 11.0183393 CALM2 12.868074 14.3045118 11.9820773 13.5509884 PSMB2 11.0948628 10.440184 10.9540363 9.9400052 IKBKG 7.63894267 7.44997399 5.96000193 7.97973957 TAB1 8.18522234 8.38331549 8.97859607 8.60332962 PRKCD 3.59931779 7.519479 6.03584382 8.00416428 RAF1 11.2970194 11.30905 10.5870461 11.5839572 CLEC4E 0 0 0 1.95233357 PSMD2 14.0123496 13.5118823 11.5047892 12.0496274 HRAS 10.0924665 9.47161425 9.45975947 10.0100245 PSMA8 #N/A #N/A #N/A #N/A CLEC6A 0 0 0 0 PSMD8 11.918867 11.6452351 11.1420049 12.2230967 UBB 11.599792 11.0899006 11.7163565 11.682468 CALM3 11.6879355 11.9176965 11.4964344 11.8091733 CD209 0 0 1.422233 7.99604973 UBA3 10.5059405 10.1629451 9.58640823 10.4589807 NFKBIA 10.649364 8.85602083 8.13576058 12.218757 NFKB2 9.77454 8.32346015 8.0606419 10.2954246 BTRC 8.92662216 9.13126536 9.86738686 8.36005695 PAK1 7.77333705 9.66586883 8.91480368 8.37885838 PSMF1 9.01714246 9.66368262 10.0056947 8.24179253 PSME2 9.97249163 9.4840777 8.76980479 10.63744 PAK3 6.93545975 3.07038933 5.88019573 2.7548875 MAP3K7 10.7790463 10.5873369 10.7271802 10.797394 PSME1 10.0362698 9.18727783 9.20261362 11.1445627 UBE2N 10.9962051 11.4486016 11.0996042 11.0431093 CLEC4C 0 0 0 2.7548875 IL1B 7.57727775 5.5428771 0.87970577 16.4900765 FYN 11.0463737 9.22937162 9.92331263 9.48480276 NFATC1 4.59514557 5.65306002 7.33333428 8.06732679 PSMD11 10.4920835 10.9185279 11.7260393 10.8055262 PSMD14 11.6597016 11.4543199 10.6866231 11.5676567 PSMB7 11.9192134 11.3511932 11.1680139 11.2072706 IKBKB 9.50694225 9.61006514 8.83753333 10.2330684 PRKACG 0 0 0 0 NFATC3 9.1454482 8.27262979 8.88950396 9.2766595 PSMA6 6.46123386 5.38162947 6.19298317 7.97148608 PSMC1 9.80922149 9.52569698 9.21693982 9.86641348 PSMA1 9.96716861 9.38646609 9.32469811 10.0613577 CUL1 10.9777593 10.8420989 11.0863021 9.94210392 CLEC4A 0 1.79493566 2.12432814 2.7548875 PSMA4 11.4206866 11.2562146 12.3125256 11.7031293 BCL10 9.56985561 9.42836017 8.35495458 9.25986093 PSMB5 10.9346934 10.645127 10.6243294 10.8124581 RELB 9.31247459 5.9112122 5.24488706 10.103419 CREBBP 9.66020987 9.70689312 10.3764293 9.21521749 PSMA3 10.8350161 10.5581433 11.0587629 11.2849166 TLR5 3.48413813 0 3.93168306 2.40871186 FOS 3.59931779 3.4409522 4.84247606 10.0901654 TICAM2 0.94860085 0 0.87970577 0 MAPK10 3.0721058 2.56803211 4.15218342 4.66789213 LY96 1.91838623 7.40871186 0 7.70963528 ATF1 8.68814538 8.77307325 8.71035875 8.40968793 MAPK14 10.6551819 10.7552298 10.3235727 11.0163417 NOD1 7.17642251 6.52732061 6.98709344 5.59723319 CTSL 10.6131172 11.610951 8.9616812 15.3276109 IRF7 7.00999653 5.42357817 6.33467553 10.1696996 MAPK3 8.21703679 9.02261749 9.2451486 8.94778303 DUSP6 6.91348784 10.2326128 5.00225245 14.2847244 UBE2D3 11.5480416 12.3529566 12.1621679 12.9455627 NOD2 0 1.15704371 4.15218342 1.28688115 TRAF3 10.0311774 9.79962161 9.70283067 10.746422 CREB1 10.4030653 9.92751132 9.8504369 10.4604559 RPS6KA1 8.2569163 6.40667272 9.59269996 13.3234264 BIRC3 7.71094416 6.79103262 4.84247606 10.1146794 DUSP3 10.094909 10.1075963 10.4587347 11.336328 IKBKE 7.49817107 7.49008872 4.96393645 10.103419 ITGAM 2.71369582 0 1.422233 11.3128886 CNPY3 9.29556233 8.82495874 8.57723998 10.6772263 ELK1 9.87048802 9.4075652 9.45112867 8.24179253 MAPK8 10.067757 10.3679825 9.66902677 9.33880322 MAPK7 7.74872957 7.23064495 7.65492239 6.96069704 MAP2K7 8.73910551 8.38331549 8.86375265 9.09529152 MAP2K4 10.0400842 9.84095097 9.74716918 9.65128494 MAPK1 11.8661198 11.9722834 11.261713 11.9525593 MAPKAPK2 10.9387857 10.7219109 9.10708627 11.132609 PELI1 6.49137212 6.98595576 8.28290308 8.69118517 MAP2K6 4.06608919 4.37364821 8.25941374 0 LGMN 9.73271014 9.81944466 9.45458719 6.15785217 IRAK2 8.15269046 6.48816149 6.51759066 11.1482223 CTSS 2.90496572 5.65306002 2.37851162 13.7168838 MAPK11 5.82273015 7.48018432 5.65849714 6.99356115 TLR3 3.22342255 2.56803211 5.75114233 2.7548875 TICAM1 6.50604967 6.29792505 5.14567746 7.05723364 IRAK4 9.01457847 8.94532678 7.58097456 9.25306744 PIK3R4 10.1299398 9.70049174 10.4168397 9.04122108 MEF2A 8.77922688 9.26160133 9.69554151 11.2521509 CD14 7.20388631 2.56803211 1.81557543 10.1146794 TLR7 0 0 0 2.40871186 RP11-330H6.5 #N/A #N/A #N/A #N/A TNIP2 8.7106687 9.19031855 8.70456077 10.1332578 TLR9 0 0 0 0 RIPK1 10.1745762 9.64603662 9.03965935 9.83043598 LBP 0 2.23266076 0.87970577 3.26603689 JUN 10.6798407 11.3987437 11.3487613 10.4186643 SARM1 5.21490191 5.72219276 5.68229237 3.94204526 BTK 0.94860085 0 2.7803101 10.4095501 IRAK1 11.0387681 11.4383812 11.5940353 12.7979533 RIPK2 8.21703679 9.23529626 7.97183092 9.07620099 TIRAP 4.35473424 6.05202456 5.75114233 6.74577515 ATF2 10.3405066 10.0749844 9.79428589 10.4619194 DUSP7 7.7548875 9.1842059 8.07868455 10.9716226 MEF2C 3.22342255 6.86913112 8.35124846 10.6296116 CD86 0 0 0 3.03210084 DUSP4 6.33449677 9.67895219 6.78240857 12.4681225 UNC93B1 8.27858884 7.73518367 6.97750891 10.2535875 MAP3K8 7.09064175 4.74899785 6.40786257 8.97687912 MAPK9 9.13121391 9.50380587 9.69700229 9.62528876 PPP2R5D 10.4265688 9.46658634 10.3497788 10.2105131 CTSK 5.14118753 11.2963714 3.23112516 5.90472493 TLR2 6.10118782 1.15704371 0 12.2497298 MAPKAPK3 7.82145512 9.29879576 9.7258945 11.8326606 TLR8 0 0 0 2.7548875 CTSB 12.4843522 14.2546042 9.63593573 15.968829 BIRC2 11.2761477 12.3209838 9.54486786 11.0558247 HSP90B1 14.0374543 14.0106776 12.9110549 13.665327 TLR6 5.21490191 5.68790052 5.75114233 9.2766595 TLR1 0 2.56803211 3.09592442 9.71433139 PIK3C3 10.6830999 9.85252951 8.73897045 9.99384416 NFKBIB 8.84758984 8.46609686 8.25545352 8.67606285 TLR10 0 0 0.87970577 2.40871186 TANK 9.51060595 9.53292081 8.04242547 11.1518664 MAP3K1 9.3782515 8.96327181 9.56098238 9.3983803 RPS6KA2 9.12166302 8.74015178 7.36299581 11.8206776 PELI2 5.21490191 6.50795317 9.18192248 5.79701298 MAP2K1 10.2412682 10.2177518 9.91707366 10.7691684 MYD88 7.21286112 8.38331549 5.14567746 8.42181238 MAP2K3 8.27858884 9.94024018 7.75922243 9.08387817 IRF3 9.48284828 8.96327181 8.63622583 10.1015293 RPS6KA3 10.3487282 10.5307477 10.59646 12.7590122 ITGB2 6.41498114 1.15704371 3.35473424 15.8830776 HIST1H2BJ 12.1617303 11.7199064 12.4860909 7.55282277 HIST1H2BB 5.59275601 10.7552298 2.37851162 5.6395216 HIST1H2BC 12.2753185 11.7204324 12.0589895 10.6018729 HIST1H2BF 10.3609787 10.4592574 9.89562072 6.56056212 HIST1H2BE 7.08087081 10.4793357 3.93168306 3.94204526 HIST1H2BI 9.18735207 11.3714772 0.87970577 4.96208625 HIST1H2BK 11.3776227 11.158433 11.6508588 10.4794468 DEFB1 0 0 0 2.7548875 HIST2H2BE 10.8945222 10.4452943 11.4317379 9.28331991 NOS2 0 0 5.85947267 4.89384756 DEFA1 #N/A #N/A #N/A #N/A PLA2G1B 0 0 0 0 DEFA1B #N/A #N/A #N/A #N/A DEFA3 0 0 0 2.40871186 RPL39 10.4573193 10.2072584 10.7293233 10.892057 LTF 0.94860085 1.15704371 0 0 H2BFS 2.23572706 1.15704371 2.12432814 2.40871186 BPIFB1 0 0 0 1.28688115 IL4 0.94860085 0 0 0 HIST1H2BG 12.0711104 11.7645565 10.1243152 8.49257426 APOA4 0 0 0 0 RNASE3 0 0 0 4.18903382 FAU 11.9971583 11.4319572 11.6546181 12.3388506 KLRD1 0 2.23266076 0.87970577 0 KLRC2 1.91838623 0 1.422233 0 CH507-9B2.1 #N/A #N/A #N/A #N/A IFNA13 #N/A #N/A #N/A #N/A CD1A 0 1.79493566 0 5.68060567 CD1C 0 0 0 5.46270675 JAK3 0.94860085 6.22843392 4.79960542 0 TNFRSF17 0.94860085 0 0 0 LAT2 3.89724043 4.45680615 4.51222689 12.1151054 CD1B 0 1.15704371 0 1.95233357 LILRA2 0 1.15704371 0 5.31433399 TEC 4.98093927 5.04701482 6.0902183 6.70653055 LILRB4 1.51096192 0 1.422233 8.96032056 OTUB1 10.2922756 9.5661492 9.72446269 10.2671144 LILRA3 0 0 0 0 TRPM4 7.23083705 8.06910063 6.55673595 8.49833066 TAP2 8.39835892 7.79246496 8.07868455 9.17634771 TNFRSF13B 0 0 0 0 NEDD4 10.4677482 11.6368783 8.85068693 9.2291072 LILRA6 0 0 3.67242534 3.26603689 ANXA1 13.3140266 14.2452912 8.46866477 10.7476308 DBNL 11.2312512 11.2771479 10.3216801 11.9117178 TAP1 10.0640152 9.0191737 8.87924628 11.5973962 IFNA2 #N/A #N/A #N/A #N/A TNFRSF21 9.36411276 9.12809746 8.97378345 10.6426294 IFNA8 0.94860085 0 0 0 IFNA1 0 1.79493566 0 0 IL2 #N/A #N/A #N/A #N/A CD6 0 0 2.12432814 4.29865832 IFNB1 0 0 0 1.95233357 LAIR1 0.94860085 0 2.37851162 9.51345127 JAK2 8.50155857 8.55393642 7.16641418 9.17275252 PTK2B 6.04154965 5.65306002 5.07553263 11.4399348 ERAP2 9.91133206 8.17137698 8.46180683 6.90989308 LILRA4 0 0 0 0 CD1E 0 0 1.422233 3.46727948 LILRB2 0 1.15704371 1.422233 2.7548875 ERAP1 9.24355484 8.56807012 8.46523987 10.229624 42437 9.17582397 8.51554216 8.92976142 8.86127305 PIK3CD 10.1251551 8.90878289 6.77135741 6.94392133 CTLA4 0 0 0 1.28688115 HMHB1 0 0 0 1.95233357 IFNE 2.49313492 5.24754781 0 0 RAG1 3.80426012 5.33842442 4.75542174 4.89384756 THEMIS 0 0 0.87970577 0 CD4 3.80426012 3.59693514 4.00898878 7.98788928 LILRA1 0 0 0 0 FGA #N/A #N/A #N/A #N/A TNFSF18 0 4.19061486 0 7.72928085 DCLRE1C 9.10231694 8.44584255 8.64230446 8.21417339 FCAMR 0.94860085 0 0 4.07038933 ORAI1 7.14842574 7.9518675 6.78240857 6.70653055 JCHAIN #N/A #N/A #N/A #N/A TRAT1 0 1.79493566 0 0 LILRB3 2.23572706 3.07038933 2.37851162 3.46727948 JAM3 7.66554911 10.3200897 10.2716264 3.94204526 FCGR1B 0 0 0 4.18903382 SKAP1 1.51096192 0 2.12432814 0 CLEC4M 0 1.15704371 0 1.28688115 TSC1 9.95509771 10.204241 9.81594361 10.0748773 CAMK4 8.9963605 6.72519582 8.00045077 6.82094479 LILRB5 0 0 1.422233 1.28688115 CLEC10A 0 0 0 1.95233357 TNFRSF11A 8.27858884 2.23266076 7.16641418 8.40356598 CSK 8.59443658 9.41017572 10.1941782 10.3069275 LIME1 5.25058267 3.98185265 4.40190347 3.80012335 IFNK 0 0 2.12432814 1.28688115 CD79A 0 1.15704371 0 0 GPR183 3.59931779 3.07038933 3.8509994 11.7520252 RNF125 4.21800615 3.07038933 8.69581987 4.82273015 PRKD2 7.97813842 7.85530455 7.65492239 6.80258099 ITK 0.94860085 0 0 2.40871186 IFNA5 #N/A #N/A #N/A #N/A CD8B 0 0 0 1.28688115 EOMES 0 1.15704371 5.79545527 8.20716078 PIK3CG 0.94860085 0 0 10.0220348 CD7 0 0 0 3.46727948 PAG1 6.50604967 8.4148966 9.55618031 11.8658067 CD79B 0 1.79493566 2.12432814 3.26603689 ICOSLG 4.98093927 5.9112122 5.5068431 9.18705509 RNF19B 8.10496561 7.519479 7.77036657 9.16914834 ADGRE1 #N/A #N/A #N/A #N/A TNFRSF13C 2.23572706 0 2.592158 1.28688115 LAX1 1.51096192 0 0.87970577 1.28688115 PRKCB 2.49313492 0 9.02580399 10.3942269 TFEB 5.14118753 6.07852445 5.68229237 9.90800225 LAT 2.90496572 0 2.12432814 3.64270157 CRACR2A #N/A #N/A #N/A #N/A PIK3CA 10.7598965 10.4478478 8.25941374 9.86418615 NLRP10 4.75221337 7.44997399 0 0 TXK 1.91838623 2.56803211 3.35473424 1.95233357 BTLA 0 0 1.81557543 2.40871186 FGB 0 0 0.87970577 0 IFNW1 #N/A #N/A #N/A #N/A CD46 11.8250701 11.3980863 9.79155363 10.949783 IFNG #N/A #N/A #N/A #N/A IFNA6 #N/A #N/A #N/A #N/A PIK3CB 8.30843005 8.03556893 8.6239912 9.46734062 LAMP3 0.94860085 1.79493566 4.88410945 2.40871186 TFE3 9.26978124 9.88111396 8.18651046 9.98977765 BTNL8 0 0 0.87970577 0 IFNA21 #N/A #N/A #N/A #N/A IFNA16 0 0 0 0 IFNA17 #N/A #N/A #N/A #N/A IFNA4 #N/A #N/A #N/A #N/A IFNA10 0 0 0 1.28688115 IFNA14 0 0 0 1.95233357 IFNA7 #N/A #N/A #N/A #N/A BTN3A1 8.94301291 6.95768249 7.41362793 8.17881422 ZAP70 1.91838623 0 1.81557543 3.46727948 SIT1 0 0 0 3.64270157 VTCN1 0 0 1.81557543 0 FCRL4 0 0 0.87970577 0 GBF1 11.0868926 11.005028 10.8364765 9.98159582 C8orf4 1.51096192 8.65888982 2.94673086 0 SLAMF1 0 0 0 1.28688115 DOCK2 8.04039932 7.52911816 0 11.6252203 PRKCE 6.56376828 8.31233844 7.67877617 5.02724254 SBNO2 10.4658521 9.71115071 8.30606169 10.6784857 HAVCR2 3.0721058 1.15704371 1.422233 12.5924734 TYROBP 2.23572706 2.56803211 0 12.0224823 CX3CR1 0.94860085 0 0.87970577 3.26603689 PSEN1 10.4197496 10.2691033 9.91330832 11.2350569 EIF2AK4 10.3569141 11.5960919 10.0255687 9.84403094 LCP1 7.61191007 3.73660488 4.28243981 15.4003945 F2RL1 8.15269046 4.68144927 8.92976142 2.7548875 APBB1IP 6.47638169 7.48018432 0 9.26322225 ICAM1 11.8280135 7.53877094 3.09592442 12.2450416 ITGAL 0.94860085 0 2.592158 8.40356598 SEMA4A 2.49313492 3.59693514 4.00898878 4.96208625 ZFPM1 5.10265813 5.8509994 5.53325185 6.29609026 STAT6 8.82416321 10.5522272 7.34082928 12.2441854 RPS6 14.3659813 14.1478202 13.657563 15.2185992 SLC11A1 3.0721058 3.07038933 2.12432814 9.80980028 ADA 4.98093927 6.29792505 7.40650266 6.66633054 ITFG2 7.76725753 7.50000529 7.82476785 6.39797405 CDH17 0 0 0 2.7548875 LFNG 9.34777637 6.22843392 4.924575 8.09792677 NOTCH2 12.8930721 12.8461054 12.3979981 12.2637064 BCL3 6.35102755 5.04701482 3.09592442 7.47346224 DLL1 4.64961546 2.56803211 6.05419729 6.97727992 MFNG 2.90496572 0 3.35473424 0 NKX2-3 0 0 4.88410945 1.28688115 LGALS1 13.9363508 14.1703781 5.24488706 13.8296623 GAPT 0 1.15704371 0 0 ABL1 11.0911907 10.8925656 10.0746767 9.49633451 CD180 0 0 0 6.5158575 PLCL2 7.90189263 7.40871186 8.6085875 8.08273452 CD244 0.94860085 1.15704371 0 8.12044526 SH2D1B 0 1.15704371 0 0 MR1 7.30879407 8.79324564 6.12536181 8.96032056 HSPD1 12.826896 13.146626 14.008791 12.6370845 DLG1 12.6482744 11.254757 9.74998672 9.31295101 KIT 4.06608919 7.30003218 8.02392065 3.26603689 TREM1 0.94860085 2.23266076 0 6.32228872 POU2F2 4.21800615 6.83832152 3.35473424 8.9561438 HLA-DRB1 0 0 6.01725384 8.36005695 HLA-DQB1 0 0 6.71493235 3.03210084 IL6 9.68317008 5.88141991 0.87970577 4.07038933 IL6R 5.5649878 6.72519582 6.70334992 13.3556195 IFNL2 #N/A #N/A #N/A #N/A IFNLR1 2.23572706 0 7.65492239 1.95233357 FFAR2 0 0 0.87970577 6.56056212 OTUD7B 10.456375 10.2458617 9.75978834 10.1929092 FFAR3 0 0 0 2.40871186 PIGR 0 0 2.12432814 9.19768359 RAB17 0 2.23266076 0 5.97223312 PRF1 1.51096192 0 1.422233 3.26603689 GCNT3 1.51096192 0 1.422233 0 C3AR1 2.49313492 0 1.422233 7.92106733 C5AR1 3.36036428 2.23266076 3.09592442 12.7315418 CR1 0 0 0.87970577 0 GPLD1 1.91838623 2.56803211 6.69167374 3.64270157 RASGRP1 4.80115866 6.50795317 7.13226837 4.89384756 PNMA1 9.77605463 9.63264993 9.45803743 9.30970371 IL1F10 #N/A #N/A #N/A #N/A IL25 0 1.15704371 0 0 IL36RN 1.51096192 0 0 6.82094479 NOTCH1 8.74537181 9.37042587 8.09650433 11.7550294 IL37 0 0 0 0 CCR2 0 0 0 0 IL1A 3.48413813 3.73660488 1.422233 8.76927586 RBPJ 9.902978 11.255483 11.15108 11.6376347 IL2RA 0 0 0.87970577 0 IL1RN 2.71369582 1.79493566 0.87970577 12.5667391 IL36G 0 0 0 3.26603689 HMGB2 11.2593372 11.0248003 11.8668771 8.10548952 IL36A #N/A #N/A #N/A #N/A KDM6B 5.21490191 5.42357817 6.53075746 8.20011392 IL36B 0 0 0 5.08915913 IL5RA 0.94860085 1.15704371 0 0 OPRM1 0 0 1.81557543 2.40871186 ELANE 0.94860085 0 0.87970577 8.32170266 BDKRB2 6.52073653 7.93014595 2.37851162 2.40871186 NPFF #N/A #N/A #N/A #N/A IL31RA 3.22342255 1.15704371 0 3.46727948 TNF 1.91838623 1.15704371 0 10.4852457 AHCY 10.8768546 10.7428231 11.4500256 10.8477543 EXO1 9.55216954 9.77952239 10.807049 7.04154965 BTN3A2 9.0325417 7.9518675 8.16977471 9.26659917 GNL1 10.0875557 9.81352469 10.0679183 10.8101539 BTN3A3 7.97280751 6.32030415 5.53325185 6.44625623 MYO1G 2.23572706 1.15704371 2.12432814 7.10318288 FOXP3 0 1.15704371 2.37851162 0 JAG1 12.2133199 7.41911748 8.09650433 11.8326606 CD8A 0 0 0.87970577 3.26603689 KDM5D 9.49401552 9.29314974 0 9.38603491 RFTN1 9.37221211 10.242924 7.64291813 11.3120775 TGFB1 8.72021005 9.03281716 6.73782194 10.5475115 UNC13D 2.90496572 1.79493566 3.09592442 7.13298804 BCL6 8.18522234 7.90809234 5.55918587 10.5265873 CXCL13 0 0 0 1.28688115 KLHL6 1.91838623 1.15704371 0 10.1202768 ADAM17 9.74055659 9.32676653 9.33409447 12.8947553 HCK 0.94860085 1.15704371 0.87970577 8.66590436 FUT7 0 0 0 4.82273015 SNAP23 10.2621066 9.70049174 9.24114898 10.6309132 PI4K2A 9.30403183 9.45394963 8.51900715 11.4158579 WAS 1.91838623 0 0 7.94649694 HFE 7.89068988 8.05577048 1.422233 1.95233357 RC3H1 9.99756057 10.2487815 9.95903112 10.3248106 TNFAIP3 9.14072754 8.30108459 6.30451104 10.5349934 PKN1 10.4544638 10.9304269 10.6433782 11.1149656 FOXJ1 1.51096192 0 0 3.46727948 CLEC4G 0 1.79493566 0 0 DUSP22 7.93504715 7.58578881 9.38930867 6.42240122 ZBTB1 10.4226745 9.85252951 8.99528664 10.9029253 TRIL #N/A #N/A #N/A #N/A CLC 0 0 0 0 C10orf54 8.45277662 8.1775192 4.61412087 8.49833066 SASH3 0 0 1.81557543 5.83364913 FZD5 6.41498114 5.50430258 8.56768994 7.58563861 TNFSF4 3.7059779 6.63865312 3.35473424 5.14893411 TRAF2 9.12166302 8.42012866 8.44799238 8.60332962 BST2 0 1.79493566 2.592158 10.5279852 ATG5 10.8165997 10.01607 10.0185897 10.9392633 IL10 0 0 0 5.75915583 APOA1 0 0 0 2.7548875 ANGPT1 4.14404637 11.2850091 2.37851162 1.28688115 APOA2 0 0 0 2.40871186 TNFRSF14 1.51096192 6.07852445 0.87970577 8.20716078 WNT5A 11.610522 13.2012847 9.39829478 3.64270157 TRIM6 7.2917693 6.54643149 6.70334992 1.95233357 REG3G 0 0 0 2.7548875 IRAK3 5.10265813 8.20789285 3.23112516 8.65051327 TNIP1 10.8276762 9.9220194 9.17147707 11.0332509 TNIP3 2.49313492 3.59693514 0.87970577 6.06802584 SKAP2 3.36036428 8.60962201 9.20057988 10.1804562 PPP2R3C 8.54874486 8.74432931 8.51573926 10.1071778 IRG1 0 0 0 4.58436125 HLA-G 0 0 0 0 FGR 2.23572706 0 0 11.7326677 CD40 0 5.46434153 3.35473424 7.08799315 KIR2DL1 #N/A #N/A #N/A #N/A KLK3 0 0 0.87970577 2.40871186 SPINK5 0 1.15704371 0 1.28688115 PGC 0 1.79493566 0 1.95233357 KLK5 0 0 0 0 KLK7 0 0 0 0 DUSP10 8.53075746 8.37260392 6.12536181 10.9115568 IRF1 9.12884499 6.9140861 6.71493235 9.41970742 SAMSN1 0 0 0 4.07038933 TRIM27 10.4799722 10.1363247 10.6961417 10.3895991 ALOX15 0 0 2.7803101 2.7548875 SIRT1 9.93610787 9.25287827 10.268694 9.39221008 IL6ST 13.406322 13.8194297 10.4423008 10.8066866 IL33 0 1.79493566 0 3.46727948 IL1RL1 1.51096192 0 0 1.95233357 IL27RA 8.28720446 7.43978934 7.51633039 8.40356598 ECM1 9.22134544 9.43095427 2.94673086 10.194683 NDFIP1 10.6418531 10.6769884 10.3357923 11.1158955 IFNL1 0.94860085 0 0 1.95233357 CD74 2.90496572 2.23266076 3.57410151 8.97687912 NLRP3 1.91838623 1.15704371 1.422233 11.0042837 IDO1 0 0 0 0 HRG 0 1.15704371 0 3.26603689 CD24 #N/A #N/A #N/A #N/A PVR 11.4501338 11.5960919 9.07825757 10.0100245 PVRL2 10.1547801 10.0483506 8.82956419 10.6960895 NCR3 0 0 0.87970577 3.26603689 CD226 2.90496572 4.37364821 1.81557543 8.96448527 CRTAM 0 0 0 3.46727948 NLRP6 0 1.15704371 0 3.64270157 GPX1 10.1323198 10.361242 9.8943479 13.6319171 CD28 1.91838623 1.15704371 0 0 ADCYAP1 0 0 0 0 VIMP 9.86619709 9.94386274 9.12670447 10.2704705 CNR1 5.25058267 0 2.7803101 8.90950311 LTA 0 0 0.87970577 5.14893411 CCR7 0.94860085 2.56803211 0 1.28688115 SPNS2 3.22342255 3.98185265 5.55918587 9.19768359 ZP4 #N/A #N/A #N/A #N/A PTPN6 4.06608919 1.79493566 4.66277517 11.601404 HPX 2.49313492 3.2675358 1.81557543 0 FCER2 0 0 0 5.36562256 HLA-DOB 0.94860085 0 2.592158 3.03210084 CCL14 0 0 0 1.95233357 CCL3 0.94860085 1.15704371 0 12.5426232 HLA-DPB1 0.94860085 4.81403765 6.2890967 1.28688115 PKHD1L1 0 0 1.422233 1.95233357 ACKR2 1.91838623 0 2.12432814 0 HLA-DOA 0 0 7.62461271 0 CCL15 0 2.23266076 0 3.03210084 CCL4 0.94860085 0 0 11.6060674 TNFRSF10C 1.91838623 5.81966818 4.15218342 3.94204526 SP2 5.53636379 5.5428771 6.01725384 5.6395216 LTB 0.94860085 1.15704371 2.37851162 5.36562256 TNFSF12- #N/A #N/A #N/A #N/A TNFSF13 HLA-DRA 0 0 2.592158 1.95233357 CRHR1 0.94860085 0 1.81557543 3.03210084 SUSD2 3.48413813 4.09000653 3.09592442 3.26603689 OAS2 2.49313492 3.73660488 1.81557543 8.02020215 C1R 8.24374524 8.89390822 5.79545527 1.28688115 ENPP1 9.99363191 10.5052657 9.78746185 3.46727948 EXOSC9 10.2837135 10.0897418 9.86868368 8.45762712 GPSM3 5.02281165 6.18010807 4.56437817 10.4307243 TNFRSF11B 6.59170933 13.3870965 1.81557543 4.18903382 HLA-DQB2 0 0 0 1.28688115 CXCL12 9.75764002 10.6726375 5.0395771 2.7548875 PTGDR2 1.91838623 2.56803211 3.09592442 3.26603689 CRIP1 2.49313492 1.79493566 1.81557543 3.26603689 TNFSF12 5.14118753 6.25190841 3.09592442 2.40871186 TNFRSF1B 2.71369582 3.73660488 0.87970577 12.6803551 OASL 2.49313492 2.56803211 0.87970577 6.58225491 KIR2DS2 #N/A #N/A #N/A #N/A KIR2DL3 0 1.15704371 0 0 FCGR3A 0 0 0 3.94204526 HLA-DMB 0.94860085 1.15704371 6.03584382 1.95233357 SMAD6 8.2569163 8.06910063 9.1114487 6.76487159 TNFSF10 5.53636379 1.79493566 0 2.40871186 TNFSF14 0 0 0 8.05961486 FCGR2B 0 0 0 5.79701298 CNIH1 10.0464283 10.7028307 9.90574801 10.350442 IRF8 0 2.23266076 6.83642913 9.20823436 RFX1 6.74926608 6.48816149 7.03408363 6.03672311 CCL3L3 0.94860085 0 0 10.7110044 IL5 0 0 0 0 PRG2 #N/A #N/A #N/A #N/A IL1R1 9.9711699 10.0143553 4.84247606 11.1518664 TNFRSF10B 10.1676189 11.2201304 9.91079261 10.7134724 HLA-C 10.5404671 11.7838577 11.104009 10.782171 IGHA1 1.51096192 0 0 2.40871186 FCAR 0 0 0 10.0319631 CCL7 0 2.23266076 0 3.64270157 ARHGDIB 4.28762004 7.52911816 1.422233 12.4604201 KIR3DL1 0 0 0 1.28688115 TRIM22 6.65949648 9.88676351 0.87970577 6.26959425 C8B 0 1.79493566 0 1.95233357 TINAGL1 5.25058267 7.75181182 0 3.03210084 ATP6V0A2 9.8431045 9.35149141 9.76676078 9.97953952 ACKR4 1.91838623 8.8288981 2.592158 2.40871186 HLA-DQA1 0.94860085 0 2.7803101 2.40871186 CD164 12.7930099 12.8111378 11.9817778 13.7601035 CCR8 0.94860085 0 0.87970577 0 TNFSF13 3.36036428 3.07038933 4.61412087 3.64270157 IL13 0 0 0 1.95233357 PRELID1 8.87061131 8.71073757 9.104887 8.6244665 PRG4 3.48413813 0 2.592158 2.7548875 CCL3L1 0 0 0 10.8985863 OAS1 2.23572706 0 0 7.84197312 C1QBP 11.8386406 11.5053848 12.9290161 11.5456402 COLEC12 0 8.40968793 8.51900715 3.03210084 ETS1 10.9543636 11.2445303 7.81941273 12.1592754 IL18RAP 0 0 2.12432814 2.40871186 RGS1 3.36036428 0 0 14.408743 CCR6 #N/A #N/A #N/A #N/A CCL23 0 0 0 3.94204526 RELT 7.52747701 7.18249368 7.33333428 9.34837408 HLA-DMA 3.7059779 4.28466219 4.08236197 3.80012335 XXbac- #N/A #N/A #N/A #N/A BPG181M17.5 CTSG 0.94860085 0 0 8.02818235 AIRE 0.94860085 2.23266076 0 2.40871186 CXCL10 0 0 1.422233 4.58436125 GZMH 0 0 0 0 CXCL8 #N/A #N/A #N/A #N/A VPREB3 0 0 1.81557543 0 CXCL9 0 0 0 0 CD70 9.45073701 1.79493566 3.35473424 7.14771372 PTAFR 3.0721058 2.23266076 3.46858332 3.64270157 DPP8 10.1652965 10.5162417 10.1134296 10.1497725 LST1 0 0 0.87970577 10.4866943 AL928654.7 #N/A #N/A #N/A #N/A FCGR3B 0 0 0 0 42430 8.07055033 5.94063661 7.348197 5.93875626 CXCL11 0 0 0 3.26603689 CEBPG 11.0118283 9.71326621 9.97955381 10.2347935 CCL18 0 0 0 4.29865832 HRH2 0 0 1.81557543 4.07038933 TNFRSF4 0.94860085 1.15704371 0 4.07038933 VIPR1 0.94860085 1.15704371 4.79960542 4.29865832 HAMP 0 2.56803211 0 3.64270157 OSM 0 0 0.87970577 6.5158575 IGHE 0 0 0 1.28688115 IFI6 6.93545975 8.93445753 7.46931621 11.7799984 OAS3 7.35032044 7.33351318 7.90267659 9.60679383 VAV1 2.23572706 1.15704371 4.88410945 10.3101924 DEFB4B #N/A #N/A #N/A #N/A HLA-F 6.91348784 5.61735726 6.58225491 0 CSF3 1.91838623 2.56803211 2.592158 5.59723319 XXbac- #N/A #N/A #N/A #N/A BPG246D15.9 TAPBP 11.5164437 10.4337628 8.67228389 11.9341405 HLA-DQA2 0 0 0 0 CCL11 #N/A #N/A #N/A #N/A NGFR 0.94860085 0 4.51222689 3.94204526 ADGRE5 #N/A #N/A #N/A #N/A KIR3DS1 #N/A #N/A #N/A #N/A IGHV3-23 #N/A #N/A #N/A #N/A CCL16 0 0 0.87970577 0 TNFSF15 0.94860085 1.15704371 1.81557543 9.13637598 IL2RG 0 1.15704371 0.87970577 1.28688115 HLA-DRB3 #N/A #N/A #N/A #N/A TNFRSF10D 9.67336208 11.3139487 7.86164526 10.8008837 CCR1 0 0 0 9.05297553 ENPP3 0 2.23266076 2.94673086 2.40871186 PTGER4 6.59170933 4.19061486 4.00898878 11.8428532 CD96 1.51096192 1.15704371 1.81557543 0 CNR2 0 0 1.422233 1.28688115 CCL4L2 0 0 0 6.21470767 TNFSF9 8.42193858 3.98185265 6.15946773 7.67962084 P2RY14 0.94860085 0 4.08236197 0 HLA-DPA1 1.91838623 5.24754781 6.20945337 3.64270157 HLA-DRB4 #N/A #N/A #N/A #N/A CXCL2 5.53636379 3.59693514 0 9.49059019 CD27 0 1.15704371 0 0 TNFRSF10A 5.50716035 6.48816149 6.64400045 8.79749942 BMP6 4.06608919 4.45680615 6.53075746 7.85990745 TNFRSF8 2.49313492 0 2.592158 3.94204526 XCL2 0 0 0 0 MADCAM1 3.0721058 0 2.12432814 2.40871186 CCL22 0 0 1.422233 2.40871186 TNFSF8 0 1.15704371 0 1.95233357 CCL19 0 0 0 0 TNFSF13B 0.94860085 1.79493566 1.422233 4.96208625 RAET1G 3.36036428 3.2675358 3.09592442 2.7548875 FASLG #N/A #N/A #N/A #N/A CCL27 #N/A #N/A #N/A #N/A CHST4 0.94860085 0 4.21878117 0 IL19 0 0 1.81557543 1.28688115 TMIGD2 0 0 0.87970577 2.40871186 SEMA4D 7.07092595 5.88141991 7.83010318 6.70653055 IL20 0 0 0 0 COL4A3BP 9.02231232 9.44122201 8.93966736 9.47027248 CXCL6 7.65892551 4.53543092 2.37851162 7.41388175 OTUD7A 1.91838623 0 5.79545527 3.80012335 IL24 3.0721058 2.23266076 0 11.5947165 CX3CL1 2.90496572 1.15704371 0 1.28688115 TNFRSF1A 10.1034452 10.0399198 7.99101157 9.86195536 CHIA 0 0 0.87970577 4.18903382 PVRL1 6.15845822 7.17022553 8.02392065 6.60377469 PF4V1 #N/A #N/A #N/A #N/A CCL17 0 0 0 3.03210084 LTB4R 5.75007049 5.50430258 6.85748343 5.72027847 CCL8 0 0 0 3.03210084 MAP4K2 6.96786027 7.85530455 7.070604 7.68964861 IL3 #N/A #N/A #N/A #N/A FTH1 8.20349484 8.87128923 6.65606727 11.5683409 IL9 0 0 0 0 CCL15-CCL14 #N/A #N/A #N/A #N/A IFITM2 1.91838623 8.35098337 6.24184018 7.48502423 CCL28 0.94860085 5.9112122 0 6.60377469 ULBP1 5.53636379 5.50430258 6.55673595 4.58436125 GPR65 0 0 0 7.92961349 PRG3 0 0 0 1.28688115 HLA-DRB5 0 0 1.81557543 3.26603689 TNFRSF18 3.36036428 0 1.422233 0 S1PR4 1.51096192 0 0.87970577 3.94204526 ICOS #N/A #N/A #N/A #N/A IL15 5.84624257 6.07852445 3.35473424 2.7548875 ULBP3 6.00045077 5.68790052 6.79337571 4.39985467 ULBP2 7.55612282 7.55773173 5.36737107 8.82059384 GZMA #N/A #N/A #N/A #N/A CCL13 0 1.79493566 0 0 LCP2 0.94860085 1.15704371 1.422233 10.6018729 CCL25 0.94860085 0 0 0 NRROS 3.48413813 1.15704371 2.37851162 9.65386615 GTPBP1 9.69773213 9.3731044 9.81995552 9.57180952 FCGR1A 0 0 0 7.21897486 MS4A2 0 0 0 1.28688115 CCL5 1.51096192 1.15704371 0 9.60145511 FYB 0 0 0 6.03672311 IK 10.9536945 10.3652945 10.5077847 10.4247017 LY75 0 0 0 4.18903382 TGFBR3 5.69960715 9.16576123 9.49205346 5.97223312 CD40LG 0 0 0.87970577 0 TNFSF11 0 0 0 2.7548875 CXCR5 0 0 0 5.20633065 AZGP1 #N/A #N/A #N/A #N/A GBP6 0.94860085 0 0.87970577 3.03210084 SBSPON 2.71369582 7.50000529 4.96393645 2.40871186 IGKV1-5 #N/A #N/A #N/A #N/A IGKV4-1 #N/A #N/A #N/A #N/A IL18 0.94860085 6.13031315 2.37851162 7.61765112 CHIT1 0 0 0.87970577 6.72628629 SLPI 0 1.15704371 0 6.83920379 GEM 7.96214411 8.24939793 5.24488706 12.5796624 IGKV3-11 #N/A #N/A #N/A #N/A IGKV5-2 #N/A #N/A #N/A #N/A TNFRSF9 8.48671437 1.15704371 3.35473424 5.86962469 CSF2 1.51096192 0 0 3.94204526 CMA1 0.94860085 0 0.87970577 1.28688115 MYLPF 2.23572706 2.56803211 2.94673086 4.29865832 SECTM1 2.23572706 5.88141991 0.87970577 3.64270157 XBP1 11.808019 10.8963021 10.0232554 11.1851852 SEMA3C 12.1494201 12.2398252 8.66035251 8.88340699 CCR10 1.51096192 3.07038933 3.23112516 0 CST7 1.51096192 2.23266076 1.81557543 0 OPRD1 0.94860085 1.15704371 3.09592442 0 IL1R2 0.94860085 2.23266076 2.12432814 5.50906239 SERPINB9 8.46797229 7.68425771 1.422233 3.03210084 ILF2 12.7860225 11.9445693 12.920297 13.2302982 CCL1 0 0 0 5.20633065 CCR5 0.94860085 0 0 2.7548875 ITGAD 0 0 0 3.64270157 C8A #N/A #N/A #N/A #N/A PXDN 12.2761273 13.2497549 9.57535015 3.64270157 SEMA7A 9.66844183 11.4581144 5.5068431 11.9876904 EDA 0 1.79493566 6.55673595 2.40871186 IL10RB 8.7822775 8.30108459 6.84699469 10.8678579 RP11-872D17.8 0 2.23266076 0 0 PDCD1LG2 9.33335664 10.8284697 0 4.82273015 IL21 0 0 0 1.28688115 CXCL14 2.71369582 3.4409522 3.67242534 3.26603689 IGKV1D-16 #N/A #N/A #N/A #N/A IL16 1.51096192 0 3.35473424 3.03210084 CR2 0 1.15704371 5.21256934 0 IFITM3 8.6013251 9.72171443 5.27649667 7.58563861 SH2D6 0 0 2.7803101 0 THBS1 16.0025212 17.3912186 3.76447355 11.068429 IKBKAP 10.4892961 10.6953414 11.3111409 10.0240177 CTSW 3.98458935 1.79493566 1.422233 5.20633065 IGSF6 0 1.15704371 2.592158 7.68964861 CCR9 0 1.79493566 2.12432814 1.95233357 CXCL1 7.46825747 6.448075 0.87970577 9.21171798 TENM1 0 1.15704371 3.8509994 0 CCL26 3.98458935 2.56803211 0 1.95233357 PNP 9.40215937 9.24996673 9.71440008 11.955174 GBP2 9.4314976 5.78790256 1.81557543 5.36562256 CD276 10.3931545 10.5757283 10.0474784 12.5067439 APLN 3.48413813 2.23266076 2.7803101 1.28688115 CCL2 9.46403515 9.54726087 2.37851162 5.02724254 AQP9 0 0 0 4.39985467 LTBR 0 10.4929748 3.8509994 9.87967514 CCL24 0 0 0 6.68664059 CCL20 2.49313492 0 0 13.1916068 CCL21 0 1.15704371 1.422233 3.46727948 NCF4 0 0 0 9.24284065 TNFRSF25 5.35226417 5.29351763 4.66277517 4.39985467 IGLL1 0 0 0 0 C1QC 0 0 0 7.31324585 LIF 9.62170392 5.78790256 1.81557543 7.31324585 FAS 6.6055536 10.3853771 4.61412087 3.26603689 RAET1L 0 0 0 0 PRKRA 9.30827076 9.37577797 9.2806084 8.96448527 ADAMDEC1 1.51096192 0 0 11.9399538 IL1RAP 9.29980329 7.24241196 6.90869284 8.90517638 TNFRSF6B #N/A #N/A #N/A #N/A IL18R1 2.49313492 1.79493566 6.50430258 5.93875626 NFIL3 8.60477559 8.22583404 7.27974985 10.4910213 ENPP2 7.53465306 10.4843094 5.36737107 1.95233357 PROCR 6.96786027 7.90068571 7.59983848 7.53060142 ENDOU 0.94860085 1.15704371 3.09592442 0 DEFB4A #N/A #N/A #N/A #N/A VTN 1.51096192 3.2675358 2.7803101 0 SAMHD1 9.32086823 9.28745844 10.3386027 11.3193955 PF4 0 0 0.87970577 1.28688115 CD274 8.06058786 9.99356115 2.592158 5.41515021 PPBP 0 0 0 7.05723364 CXCL5 7.2917693 4.09000653 0.87970577 6.37312616 KAAG1 0 0 1.422233 0 CFP 3.0721058 1.79493566 1.81557543 4.82273015 IRAK1BP1 6.08172309 5.8509994 7.07948478 5.20633065 IGF1R 9.87762157 10.8991001 11.5052062 5.14893411 BPI 0 2.83995959 0 2.40871186 SMAD3 11.1257041 9.53772316 9.02812708 6.62497818 CXCL3 4.53853816 3.2675358 2.12432814 10.5377814 CLNK #N/A #N/A #N/A #N/A IL17A 0.94860085 0 0.87970577 1.28688115 IL26 #N/A #N/A #N/A #N/A CYP11B1 0 0 0.87970577 2.40871186 CMKLR1 0 0 0 6.42240122 IL17B 0 0 0.87970577 3.64270157 TCF12 10.6560047 11.2569399 9.82129566 12.0510968 FCGRT 6.1771205 9.32952728 7.64889681 12.8887547 VPREB1 0 0 0 0 CCR4 #N/A #N/A #N/A #N/A IL4R 9.72325137 9.29879576 7.37033868 10.6098528 TNFAIP1 9.49030939 10.1204323 9.39289696 9.18705509 ZEB1 10.1358888 11.1615413 9.80245174 10.9560567 IL32 8.82416321 3.98185265 1.81557543 3.46727948 TCF7 6.23150921 5.8509994 7.85118684 5.41515021 CEBPB 9.8269933 9.25287827 7.41362793 11.5697085 MBP 7.49817107 4.37364821 6.25776497 12.2737869 CYSLTR2 0 0 0 3.80012335 OPRK1 0 1.15704371 4.56437817 0 BMPR1A 10.4275433 10.2251954 9.66604643 8.29558529 CEACAM8 0 1.15704371 0 0 CIITA 3.80426012 2.23266076 3.35473424 2.7548875 IL7 4.59514557 4.68144927 2.592158 1.95233357 TINAG 0 0 0 0 IL22 0 0 0 2.40871186 C1QB 0 0 0 3.26603689 CFD 3.0721058 1.79493566 6.01725384 10.889869 IGHG1 0 1.79493566 0.87970577 0 CFB 4.06608919 3.2675358 4.21878117 3.46727948 C2 1.51096192 1.15704371 2.37851162 4.39985467 C1QA 0 0 0 9.13267965 RGCC 2.23572706 4.74899785 4.96393645 13.901179 C7 0 0 0 0 IGHG4 0 0 0 1.28688115 C4B 0.94860085 1.79493566 0 3.64270157 C4A 2.49313492 0 2.592158 1.95233357 CLU 6.74926608 7.79246496 9.73159057 3.03210084 CFH 5.14118753 9.93116594 0.87970577 1.95233357 C5 7.56323441 7.38758657 3.23112516 5.46270675 IGHG2 #N/A #N/A #N/A #N/A C4B_2 #N/A #N/A #N/A #N/A CFHR1 0 1.15704371 1.81557543 1.28688115 C1S 8.85046816 10.8459683 4.66277517 3.26603689 C9 0.94860085 1.15704371 0 3.46727948 C8G 2.90496572 2.23266076 3.09592442 4.39985467 CFHR5 #N/A #N/A #N/A #N/A VSIG4 0 0 0 4.58436125 SUSD4 5.17871464 4.37364821 6.22573765 1.28688115 C4BPB 0 0 0 2.40871186 IGHV3OR16-9 #N/A #N/A #N/A #N/A CFI 4.89384756 3.07038933 0.87970577 2.40871186 C4BPA 0 0 0 1.28688115 CD55 10.0131691 9.17809214 8.76980479 9.23599027 IGLL5 #N/A #N/A #N/A #N/A C1RL 7.04078287 7.83983365 5.11103131 4.49505553 ST6GAL1 6.68565988 5.04701482 7.40650266 10.0633007 SH2D1A #N/A #N/A #N/A #N/A PDCD1 0 1.15704371 1.422233 0 LY86 0 0 0 7.80535695 YTHDF2 10.8364765 10.607996 10.8331668 10.7048028 CD83 7.2917693 5.9112122 7.24830712 11.9753894 BLNK 0 0 0.87970577 3.03210084 TREM2 2.23572706 1.15704371 0 12.3081172 GPI 11.7466991 11.3132459 11.913125 11.3750829 MNX1 0.94860085 0 7.86684618 3.26603689 BST1 8.95384723 7.80844941 2.37851162 7.96318509 POU2AF1 0 0 0 3.46727948 BCL2 7.951343 6.10454634 7.7977912 10.1893675 TRAF3IP2 8.76085299 8.63669712 6.55673595 8.52109001 PAX5 0 0 2.94673086 3.94204526 MS4A1 0 0 0 2.7548875 EBI3 4.21800615 2.83995959 1.422233 8.91808803 DEFB103B #N/A #N/A #N/A #N/A DEFB103A #N/A #N/A #N/A #N/A GAS6 11.0157077 13.0965307 5.97933945 6.58225491 TGFB3 6.41498114 5.04701482 6.20945337 9.82359016 TGFB2 10.7994435 8.08884123 3.93168306 5.68060567 CUEDC2 9.05283972 9.17809214 8.6270596 9.35155766 IGHD #N/A #N/A #N/A #N/A IL13RA2 0 7.54828248 0 6.21470767 INPP5D 1.91838623 3.4409522 1.422233 10.5571669 SLA2 0.94860085 0 0.87970577 3.26603689 DEFA4 #N/A #N/A #N/A #N/A CST9 0 0 0 0 AZU1 0 0 0.87970577 9.92088874 VIP 0 0 0 0 ADM 9.6301579 11.6819719 6.55673595 8.75495429 SEMG2 0 0 0 0 ANG 4.14404637 4.45680615 3.35473424 2.40871186 DEFA6 #N/A #N/A #N/A #N/A APP 12.8625192 13.6372373 11.6444422 11.3617519 TAC1 0 1.15704371 2.592158 1.28688115 NPY 0 0 0 4.07038933 RNASE7 0.94860085 0 0 0 DEFA5 #N/A #N/A #N/A #N/A PLA2G6 5.28540222 5.38162947 5.83844759 6.03672311 SEMG1 0 0 0 0 CALCA 0.94860085 0 0 3.03210084 BPIFA1 #N/A #N/A #N/A #N/A PR0S1 9.32294213 7.79246496 8.64835758 9.22216698 CHGA 0 1.79493566 3.35473424 4.39985467 HMOX1 8.2699682 9.69620252 10.2459448 12.5622901 NR4A3 2.71369582 5.099716 5.27649667 7.33904828 LGALS9 0.94860085 2.23266076 2.94673086 9.77945673 CD300A 0 0 0.87970577 8.83428142 FER 9.93884446 10.5319467 9.55618031 9.05297553 GFI1 4.64961546 2.23266076 6.63183185 9.00537192 NFKBIL1 7.25729355 7.04111154 7.27192984 8.75495429 TYRO3 8.90728127 9.29029538 9.14391886 7.33904828 ARRB2 6.91348784 6.448075 9.4886837 11.0519226 LGR4 10.821774 9.83899902 10.9601251 6.34801991 CACTIN 8.98848588 8.6676438 8.32129678 8.74533819 IRF4 0.94860085 2.23266076 3.09592442 3.64270157 NLRP2P #N/A #N/A #N/A #N/A PIK3AP1 1.51096192 2.83995959 7.24031433 11.0856982 CYBA 9.53964351 10.0766286 8.5929802 12.8387017 UBQLN1 12.0285415 12.0046769 10.7659325 11.577188 FLOT1 10.2368394 10.7386665 9.47173617 10.6835386 WDFY1 10.734227 11.3313089 9.88028758 11.0253195 CAV1 12.8010879 13.8381344 7.11488753 10.6151422 PTPN22 5.95814667 3.59693514 1.81557543 6.64573048 S100A14 0 1.15704371 0 2.7548875 NR1D1 5.06350294 6.29792505 4.66277517 3.46727948 DAB2IP 7.20388631 9.24410215 8.7361313 4.58436125 RAB7B #N/A #N/A #N/A #N/A NR1H3 5.69960715 5.68790052 6.58225491 7.3262497 RSAD2 0 1.15704371 0 6.58225491 MX1 5.86937792 5.38162947 2.94673086 2.40871186 ISG15 7.11977116 8.56807012 5.30742853 9.49920809 TRIM56 9.11444511 8.95968323 7.41362793 9.19414124 SP100 9.69449719 10.3018848 2.94673086 10.1750879 MEFV 1.51096192 0 0 7.33904828 TRIM21 7.71726515 7.98031098 7.070604 9.51629099 GCH1 7.78555055 4.87578006 8.37695017 8.73562372 UBD #N/A #N/A #N/A #N/A CXCL16 3.0721058 3.4409522 6.65606727 7.00977264 SNCA 4.53853816 2.83995959 7.73667252 0 CALCOCO2 9.88612332 10.5089337 9.95415268 10.5488893 CYP27B1 3.89724043 4.37364821 4.84247606 6.12845838 IFITM1 2.23572706 7.24241196 3.76447355 3.03210084 KYNU 0 2.56803211 2.37851162 10.9539709 CITED1 3.0721058 1.15704371 5.58466191 0 SEC61A1 13.0285277 13.3817728 11.7865719 12.7032266 SLC30A8 0 1.15704371 0.87970577 1.28688115 ADAMTS13 4.89384756 4.68144927 6.19298317 3.80012335 DNAJA3 10.516025 10.3004784 10.4783854 10.6256815 ADAM8 4.70154906 5.29351763 4.88410945 6.80258099 FGF7 1.91838623 8.84830996 1.81557543 3.26603689 FGF17 0 0 1.81557543 3.03210084 FGF20 0 1.15704371 1.81557543 0 PEBP1 11.7032547 11.8879669 11.8073267 10.7880494 RICTOR 9.62846377 10.3773841 9.83991236 11.3990749 GSK3B 10.5636253 11.0162372 10.2095996 10.280504 FGF16 #N/A #N/A #N/A #N/A CD80 0.94860085 0 1.81557543 1.95233357 FRS2 9.28701972 9.59633886 9.25507579 8.52109001 RASAL3 0 1.15704371 0.87970577 5.46270675 SHC2 1.51096192 5.099716 5.07553263 6.70653055 NRG2 3.36036428 1.79493566 5.14567746 3.03210084 FRS3 3.80426012 4.9349882 5.30742853 5.36562256 CUL3 10.390169 10.736588 10.7135498 10.4262123 VAV2 8.49785184 9.00539999 7.33333428 6.42240122 RPS6KB2 8.90728127 8.91984656 8.68411741 9.46734062 FGF5 5.5649878 11.3484681 3.76447355 0 LAMTOR2 8.92389197 8.30108459 8.6453342 10.5010609 FOXO4 7.61867915 6.65635335 8.50243404 7.47346224 GRB2 10.0615197 10.4195494 10.0656585 11.6774158 TEK 1.91838623 7.37695017 2.7803101 0 MAP2K2 11.0285623 10.6136882 10.3395383 10.6005355 FGFR3 6.15845822 5.04701482 8.49908847 3.64270157 MTOR 11.6654736 11.0718377 11.9370942 10.6098528 PHLPP2 10.2522751 9.67678573 9.15668987 7.90388185 CDKN1B 10.1346958 9.81747937 9.60984359 8.14261766 RASGRF1 2.23572706 3.2675358 1.81557543 5.72027847 FOXO1 4.89384756 7.05452292 9.098269 6.39797405 GRIN2A 6.96786027 0 1.81557543 0 RASA1 11.004691 11.0510254 9.17357721 12.131828 SPTBN5 5.67355642 3.59693514 3.8509994 7.75828985 NEFL 0 4.9349882 10.6181836 1.95233357 GAB2 5.77478706 8.97036478 6.63183185 9.73150572 AKT1S1 9.32712595 9.06307145 8.80542145 8.98507343 PHLPP1 9.12884499 8.25526467 8.80271022 8.84784036 SPTBN2 7.69167374 5.5428771 10.1733648 5.59723319 GAB1 7.02036885 7.68425771 9.38750041 5.31433399 PDGFB 5.44724857 1.15704371 2.37851162 6.68664059 RASA4 6.12060077 5.81966818 5.21256934 7.59633886 PDGFA 7.26594316 7.66682759 5.27649667 12.983423 RAPGEF2 9.08273452 10.333938 10.4630339 9.05688153 TNRC6B 10.2009476 11.0618842 10.8503197 9.85302879 KSR1 4.59514557 6.60243906 7.57470705 6.12845838 RASA3 8.99112498 10.6406788 7.40650266 12.5166825 GSK3A 8.53438071 7.83206719 7.80322704 8.58725246 SYNGAP1 6.46123386 6.82273015 6.58225491 6.42240122 FGFR4 1.91838623 2.56803211 7.57470705 5.08915913 EGFR 10.5993922 12.0393201 8.0606419 4.66789213 TRIB3 8.19893609 8.25526467 7.62461271 9.85525783 AGO4 8.51258246 8.14644139 8.78907713 9.13637598 LAMTOR3 8.58402294 9.43866712 9.32469811 10.1479426 PAQR3 9.2805852 9.49890903 10.1079624 8.78816366 RASGRF2 3.89724043 8.28974227 7.13226837 5.02724254 PTPRA 9.53243385 9.95644876 9.77231457 9.61474665 MDM2 10.3640252 12.0899768 11.3445789 10.4953354 BRAF 8.75157753 9.43866712 9.74716918 9.45852965 RASA2 9.94156119 10.229648 8.64230446 9.92088874 IL17RD 6.56376828 4.81403765 7.9572762 4.82273015 PIK3R1 8.2125207 10.6148203 8.55485741 10.194683 ACTN2 0 0 5.30742853 3.26603689 FGF1 7.64565843 9.63711389 0 3.26603689 FGFR2 9.99494737 0 9.26101359 0 AGO1 10.4148649 10.1268077 11.1842369 9.93153533 PTK2 10.7660568 10.8206178 10.8542451 9.54430764 CAMK2D 8.82416321 11.7989132 9.57216966 11.0577684 AGO3 9.56985561 9.4840777 9.73159057 9.42273759 GRAP2 2.23572706 0 0.87970577 3.26603689 FGF19 0 0 0 1.28688115 EREG 2.71369582 9.78357124 1.422233 1.28688115 GRIN2C 2.90496572 3.59693514 4.00898878 3.64270157 GRIN2B 1.51096192 0 3.57410151 1.28688115 FGF23 0 0 2.37851162 0 ERBB3 2.71369582 4.74899785 7.39934202 3.64270157 CASP9 6.98913901 6.58406053 7.43471162 7.78672704 NF1 9.82553125 11.5078293 11.87399 11.1527792 BRAP 9.21235047 9.24117282 9.19231748 9.48769937 JAK1 12.3980569 12.1456074 10.6792602 10.8689691 FGF6 #N/A #N/A #N/A #N/A BTC 0 0 0 3.46727948 CDKN1A 8.98584194 12.6152664 6.22573765 15.0672528 CSF2RA #N/A #N/A #N/A #N/A KBTBD7 7.26594316 7.21878117 8.44107674 6.76487159 MAPKAP1 11.5250901 11.2334879 10.3064605 11.0999329 RASAL1 0 0 3.46858332 3.26603689 YWHAB 12.0896325 12.5520999 11.915323 12.5457464 PDGFRB 9.06037169 11.0392412 1.422233 5.31433399 EGF 5.67355642 6.67383906 4.924575 0 FGFR1 10.734227 11.7283202 9.20057988 9.918744 CAMK2B 3.22342255 3.73660488 4.88410945 6.00495076 FGF9 2.23572706 2.23266076 5.33771109 4.7473874 AKAP9 11.3170734 11.3354462 10.7749435 10.1929092 IL3RA #N/A #N/A #N/A #N/A NRG4 3.98458935 3.73660488 6.24184018 3.46727948 RASGEF1A 2.23572706 2.23266076 7.39934202 4.18903382 PDGFRA 3.89724043 10.7542027 5.55918587 6.80258099 PIK3R2 0 0 0 2.7548875 AGO2 8.48300958 9.85637884 10.265744 12.7927049 SPTA1 0 0 0 1.95233357 MARK3 10.6326227 10.6091418 10.3636311 11.230747 DUSP5 8.23491321 10.1582815 7.08841725 12.6657578 DLG4 8.01992426 8.13386145 5.96000193 8.60332962 AKT1 11.0285623 11.3980863 9.78608989 10.5681366 IRS2 8.65538761 9.26451297 8.04242547 11.2948505 THEM4 7.72996056 7.44997399 8.34753279 8.65563805 LCK 0 0 0 0 IRS1 8.9565504 11.0915346 7.17472599 5.93875626 SPTBN1 12.9891106 13.4034408 12.5959544 10.9623032 FGF4 0 0 0 0 IL2RB 2.23572706 2.23266076 1.81557543 0 FGF3 0 0 0 0 DUSP9 1.91838623 2.56803211 7.78135971 5.55397481 SPTBN4 3.7059779 4.45680615 6.37903173 3.46727948 PLCG1 9.71849863 10.1981995 10.0645272 7.41388175 RBX1 9.24797497 8.63669712 8.93966736 9.02541645 MOV10 9.10231694 8.87887858 9.12887076 9.60412694 FGF2 10.7896559 13.7888386 8.13576058 7.92106733 ERBB2 9.18962692 9.92386227 9.44594598 3.46727948 RAC1 11.475242 11.417726 10.433575 10.2671144 WDR83 5.5649878 5.33842442 6.12536181 5.26115467 BAD 8.51625158 8.31233844 7.61845892 8.24863919 MLST8 8.56292926 8.08884123 9.50211575 8.66590436 RASAL2 10.8553591 10.4273233 9.28255564 10.9612688 CAMK2G 9.09745278 9.36503196 9.34717842 7.97148608 SPRED1 9.82257083 11.2349671 8.49908847 10.8533641 CD19 0 0 4.34340782 3.46727948 SHC3 2.23572706 6.46825747 3.09592442 5.50906239 NRG1 9.67828322 10.0881124 3.93168306 11.5940493 CSF2RB 0 2.56803211 1.422233 8.69620252 PTPN11 12.452267 12.7138784 12.2660955 11.8246843 KLB 3.0721058 4.61058196 5.55918587 3.94204526 TNRC6A 10.5233071 10.6910456 10.3414076 8.92662216 RASGRP4 1.91838623 1.15704371 1.81557543 2.7548875 SPTAN1 13.0493381 13.1976928 12.0691678 11.7574234 FOXO3 9.61829373 10.0930081 10.2881855 10.8843995 HBEGF 9.35801377 8.49597491 6.86777294 12.6686258 SOS1 8.66530038 9.71748794 9.79292041 8.75975506 PPP5C 10.3374101 10.0195073 10.4247962 9.6383454 SPTB 4.21800615 6.13031315 8.00517539 3.80012335 FGF8 0.94860085 0 0 1.95233357 PTEN 11.1352476 11.237915 10.5511891 9.86418615 VAV3 3.59931779 1.15704371 7.37764436 13.433562 ARAF 9.27195318 8.94892201 9.06926178 8.87458182 NCAM1 1.51096192 4.87578006 8.71035875 11.8074395 FGF22 0.94860085 2.23266076 2.37851162 1.95233357 ERBB4 0.94860085 0 6.668034 5.02724254 TSC2 10.1477264 9.88487261 10.4265478 9.74121416 PEA15 11.8415565 12.568006 9.1114487 12.5650283 GRIN1 2.23572706 2.23266076 2.37851162 4.07038933 RASGRP3 2.23572706 4.74899785 4.21878117 10.8600705 PRKCQ 1.91838623 1.15704371 7.54256761 4.49505553 SHC1 11.3044426 11.8657371 8.53869335 10.8556082 GRIN2D 2.49313492 5.15055968 5.11103131 7.87768291 KL 3.0721058 0 0 3.64270157 TNRC6C 6.87982827 8.85602083 8.49908847 6.76487159 CAMK2A 4.48026512 3.59693514 0.87970577 6.34801991 NR4A1 3.36036428 6.20457114 6.80426012 3.26603689 FGF10 0 1.15704371 1.422233 1.28688115 FGF18 3.36036428 1.15704371 2.592158 3.46727948 KITLG 11.3816349 12.200304 9.21693982 10.0748773 BRK1 10.8632803 10.6395668 9.96751448 11.7241131 FCGR2A 0.94860085 0 0.87970577 7.26011977 ARPC1A 11.4094281 11.1380542 10.3718746 10.1858046 MYO1C 12.3274965 12.7106988 9.70863559 10.6683355 MYO10 10.0714892 12.7450482 10.5308745 12.2883643 NCK1 8.94573644 9.06971828 8.43758564 9.83951875 PLPP4 #N/A #N/A #N/A #N/A NCKIPSD 7.77333705 8.03556893 8.68116812 9.53595573 ARPC1B 10.7529409 10.6910456 7.52293456 12.0559704 CFL1 13.9592802 13.6097536 11.9441776 13.4709181 ELMO2 8.90728127 9.37042587 8.89714965 11.6830999 HSP90AA1 14.279073 14.2484939 14.6492871 14.1134581 CYFIP2 3.48413813 8.03556893 9.97835296 4.39985467 CRK 11.7028523 11.8931195 10.8555537 11.6140242 CDC42 12.6557521 12.5990155 11.8944881 13.0138147 ACTR3 13.3344912 13.701405 11.7109528 14.4603189 ARPC2 12.6139207 12.9335136 10.6350288 13.7968326 ELMO1 0.94860085 0 5.24488706 6.72628629 CD3G 0 0 0 0 ABI1 10.2642784 9.96892594 9.18816846 11.4941156 ARPC5 13.3230562 12.9068944 10.4944156 13.2129401 WASF2 10.5287471 10.2132622 9.85698569 10.412591 HSP90AB1 14.1016811 14.071661 14.7075921 14.9602617 DOCK1 10.8016922 11.043458 10.0825083 0 ARPC4 10.7056929 10.9185279 8.63926835 12.5619466 BAIAP2 8.85337194 8.03556893 7.80322704 9.88626053 CD247 1.91838623 0 0 0 ACTR2 11.8909748 13.0225707 11.6519845 13.1631921 WASL 9.61829373 9.70689312 8.98575657 8.26893961 WIPF3 2.49313492 2.83995959 5.42458623 3.03210084 WIPF1 6.41498114 8.92718536 7.05245937 9.22216698 ACTG1 15.8482085 16.4399607 14.5365478 15.7377419 WIPF2 9.28701972 9.47660446 9.113638 9.50491828 PLD2 7.37469175 7.31124879 7.62461271 7.88642821 ARPC3 11.1883539 11.0417755 10.319785 12.2514321 LIMK1 9.49215363 10.4554608 7.91778976 10.9286738 MYH2 0 1.15704371 0 0 YES1 11.2467406 10.9083851 10.2147077 9.40143421 ACTB 16.207816 16.5133911 13.9956603 15.7744085 NCKAP1 12.5558186 12.934651 11.9367852 9.07620099 CYFIP1 11.2262376 11.6770898 10.7477398 13.3855618 NCKAP1L 2.49313492 1.15704371 0.87970577 12.8173235 DDX58 8.49785184 8.61871585 7.05245937 8.41578401 IFIH1 6.10118782 4.68144927 6.2890967 8.77402928 LSM14A 10.6190828 10.4038855 10.5688302 10.6164661 TSPAN6 8.47175649 8.80125568 11.0587629 6.99356115 TKFC #N/A #N/A #N/A #N/A DHX58 3.89724043 5.9692426 3.57410151 6.96069704 NLRX1 7.11019618 7.8242587 8.33632803 8.34739991 IL18BP 5.28540222 5.46434153 5.39643353 5.50906239 RORC 0 0 0.87970577 2.40871186 ATP7A 8.65867564 9.23232498 9.30569698 9.54708732 TUBB 14.292661 14.2343504 13.861718 12.7097387 GZMB 0 0 0 5.6395216 CLEC2A #N/A #N/A #N/A #N/A LYST 9.96181141 10.1981995 8.7753469 13.2504332 SLAMF7 0.94860085 0 0 10.082535 PRDX1 13.0130836 12.705114 13.3457919 12.8387017 TUBB4B 12.5507035 12.8332439 11.8522174 11.7460062 NCR1 0 0 0 3.80012335 PIK3R6 0 0 0 3.94204526 SERPINB4 2.23572706 1.79493566 0 3.80012335 CADM1 6.02125762 8.92350577 11.1462823 9.32916846 SPON2 2.23572706 8.06242397 3.93168306 3.03210084 S100A13 8.99112498 9.49151242 7.7868577 6.60377469 MILR1 0 1.79493566 0 8.73562372 CPLX2 1.51096192 0 2.94673086 2.40871186 PLA2G3 2.71369582 1.15704371 1.81557543 0 MRGPRX2 0 0 0 0 GATA2 8.09032418 10.3598923 8.96895473 4.7473874 FES 2.71369582 6.80696843 4.34340782 6.8750428 STXBP2 3.0721058 5.65306002 5.99842119 9.09905845 C12orf4 9.93747681 9.87164347 9.74716918 9.24968236 RAC2 4.41886458 4.99186193 0.87970577 10.9350398 CD84 0 1.15704371 0 8.10548952 RABGEF1 5.5649878 4.28466219 3.8509994 5.46270675 FOXF1 0 8.9050861 4.56437817 5.55397481 ADORA2B 8.5198721 5.99729241 8.6085875 8.86573327 VAMP7 #N/A #N/A #N/A #N/A VAMP2 5.53636379 5.24754781 6.43612852 5.83364913 STX4 8.6218321 8.92350577 8.14435234 10.5681366 STXBP3 10.1155509 10.1379005 9.74998672 11.5539364 ANXA3 9.54859075 7.02746372 6.92872562 1.28688115 PRAM1 2.23572706 1.79493566 1.422233 3.26603689 ABR 11.0832001 10.3800497 9.54810905 12.4011062 BCR 9.3681572 10.0600609 10.603478 9.91445988 RAB27A 8.2569163 7.60421962 6.0902183 7.11821435 CORO1A 3.59931779 5.46434153 5.58466191 12.2222304 KLRF2 0 0 0.87970577 0 LAMP1 12.2836556 12.5906759 11.1648567 12.3938087 AP1G1 12.0285415 11.3388812 11.3749797 11.4143417 LEXM #N/A #N/A #N/A #N/A LEF1 5.38474059 3.07038933 8.05609576 1.28688115 BATF 0 0 0 7.13298804 DEFB125 #N/A #N/A #N/A #N/A KIR2DS4 0 0 0 0 DEFB126 #N/A #N/A #N/A #N/A DEFB127 0 0 0 2.40871186 NLRP2 0 0 0.87970577 0 DEFB128 0 0 0 1.95233357 DEFB129 #N/A #N/A #N/A #N/A TNK1 4.64961546 3.86393845 2.7803101 4.89384756 TREML1 0 0 0 5.93875626 CRISP3 #N/A #N/A #N/A #N/A CD300E 0 0 0 1.28688115 DEFB110 0 0 0 0 TBKBP1 5.82273015 7.32237887 8.47549026 8.54345722 AGER 4.70154906 2.56803211 3.67242534 4.96208625 DEFB112 #N/A #N/A #N/A #N/A PDE1A 2.23572706 4.68144927 2.12432814 0 LCN2 0 0 0 1.95233357 PRSS2 #N/A #N/A #N/A #N/A DEFB132 #N/A #N/A #N/A #N/A PRKCA 10.3951378 10.8255313 9.25507579 9.8949996 TRIM15 0 0 1.422233 1.95233357 NLRP4 0 0 0 0 XRCC5 13.4627157 13.415376 13.299115 13.1233293 UBA7 6.08172309 6.94333532 2.12432814 8.45174687 IPO7 12.278281 12.9464165 12.4805933 12.4407939 ADCY7 6.52073653 7.90809234 6.0902183 8.20011392 TRIM26 9.5768811 9.33505533 9.21693982 9.04908617 DDOST 12.5480247 11.977584 11.5494959 12.5071009 CAPZA2 12.0926977 12.0287176 10.7314548 12.7724053 PDE1B 0 0 5.4799419 9.23943146 PRKD1 7.69807954 9.3542053 7.60607203 0 ANKHD1 5.31903982 5.099716 6.19298317 5.36562256 SIRT2 9.34777637 9.07961811 8.66334462 10.7035662 PYDC2 #N/A #N/A #N/A #N/A POLR3F 8.68814538 9.06638524 8.72471848 7.80535695 ARHGEF2 11.2155937 10.4414607 9.44941693 13.4721958 MID2 5.47767733 7.44997399 7.70804925 4.58436125 RNF135 6.64616266 7.50000529 7.80322704 9.20823436 S100A7 0 0 0 0 ADAM15 10.0247657 10.1252197 9.20057988 10.2157514 POLR3E 9.72956976 9.40494994 10.2055 9.47901224 LILRA5 0 0 0 1.28688115 POLR2K 9.92102268 9.39175913 9.26692706 10.199979 DEFB116 #N/A #N/A #N/A #N/A IFIT5 9.48844271 10.1410598 8.86114896 7.2465981 DEFB115 0 0 0 0 IFNL3 #N/A #N/A #N/A #N/A UBE2L6 8.17137698 7.87054967 6.59484709 8.12789118 OTULIN #N/A #N/A #N/A #N/A CYBB 0.94860085 0 3.8509994 11.1140286 DTX4 0.94860085 5.65306002 5.63430284 8.89214813 IRGM 1.91838623 2.56803211 0 2.40871186 HERC5 4.84799691 3.59693514 9.2451486 5.90472493 TRIM11 8.79135827 8.68502907 8.9173124 8.96448527 AXL 13.0707868 13.6396087 3.67242534 6.29609026 APOL1 2.71369582 3.07038933 0 6.39797405 S100A9 0.94860085 1.15704371 0 10.8800044 EIF2AK2 9.78821261 10.8087712 10.7221757 9.90151557 S100A12 0 0 0 5.20633065 ZBP1 0 0 1.422233 0 APOBEC3A 0 0 0.87970577 0 APOBEC3H 0 0 0 0 DEFB131 0 0 1.422233 0 XRCC6 13.6841591 12.9627749 13.7641625 13.0925722 HMGB3 10.2077465 9.75503778 10.1079624 8.59260653 SIGLEC14 0 0 0 0 TRIM8 10.1107182 10.1906025 8.63926835 11.0173443 POLR2L 10.1203545 10.7695651 9.65408104 10.1750879 CASP10 2.23572706 4.53543092 7.27192984 8.12044526 ADCY8 1.51096192 0 0 10.2105131 BPIFB3 0 0 0.87970577 2.40871186 TRIM28 12.836798 12.3199402 12.6263319 11.4955503 TRIM35 8.69463647 8.97036478 8.4093485 8.99729241 NCF2 3.98458935 5.46434153 2.12432814 9.03729985 POLR2E 10.7467326 10.3933368 10.6976018 10.5279852 ADCY3 7.70452619 9.86785014 8.83222546 10.2518966 TOLLIP 8.9565504 9.23529626 7.94263179 10.5082008 CD300LB 0.94860085 0 0 7.27360913 PADI4 1.51096192 1.15704371 0 0 LRRFIP1 10.0752117 10.7480083 9.33035672 10.7584398 TRIM31 1.51096192 1.79493566 0 2.7548875 TRIM32 9.50509698 9.60093501 8.5961152 5.41515021 DEFB118 0 0 0 0 RNF216 10.6992688 10.3380678 10.0474784 9.81440622 NAIP 4.89384756 4.28466219 4.08236197 4.7473874 ATG12 10.3435966 10.3747026 9.45631334 9.99791335 PIN1 10.6190828 10.1331551 10.3827969 10.4692552 PRKCSH 12.3009817 11.5845539 10.7825232 11.258937 BLK 0.94860085 2.83995959 1.81557543 2.7548875 ITCH 11.5565013 11.4949456 10.9094131 11.7876414 DEFB104B #N/A #N/A #N/A #N/A ADCY1 4.59514557 3.07038933 9.50211575 8.82518141 MST1R 2.90496572 1.79493566 4.28243981 1.95233357 GZMM 0 0 2.37851162 2.7548875 PPARG 4.53853816 6.63865312 8.04242547 10.4837956 SIRPB1 0 1.15704371 0.87970577 2.7548875 TNK2 8.46417814 8.9050861 7.99101157 7.71945728 DDX60 6.94637997 7.74355536 7.03408363 9.36732738 NCF1 0 0 0 9.86862195 BMX 0 0 0 0 DEFB108B 0 0 0.87970577 0 TRIM62 5.47767733 6.22843392 6.17632277 3.94204526 IL1RL2 2.90496572 3.07038933 0.87970577 2.40871186 LGALS3 9.83140226 9.82338316 7.02480723 12.3864715 TRIM25 8.64205169 9.73011345 9.43548275 8.2349611 PRKAR1A 12.1900469 12.8103969 11.7609902 12.9310385 SRPK2 10.1441866 9.84481559 9.62371692 8.50973542 SDHAF4 #N/A #N/A #N/A #N/A DEFB123 #N/A #N/A #N/A #N/A ADCY5 3.59931779 3.98185265 4.45811948 1.95233357 ADARB1 7.52747701 8.00129559 8.32880954 11.6020725 PTX3 9.11444511 10.7978155 4.00898878 7.14771372 BCL2L1 9.4526325 10.627242 8.19888699 10.1277107 S100B 0 0 0.87970577 4.07038933 CRCP 9.8431045 9.64380209 8.78907713 9.83497662 NLRP1 6.26659917 8.92350577 7.42071818 3.26603689 TXN 12.2693722 12.0257348 11.737429 12.0224823 PRKAR1B 7.77945673 8.08225551 8.13576058 7.38939472 PTK6 0.94860085 2.23266076 1.422233 5.75915583 IL34 1.51096192 1.79493566 0.87970577 2.7548875 POLR2F 10.045159 9.21747308 10.0290525 9.95887167 TREX1 7.61867915 6.40667272 4.79960542 6.70653055 APOBEC3C 8.5052558 9.04636009 8.08316017 7.10318288 F12 4.35473424 3.73660488 5.79545527 1.28688115 FRK 3.0721058 3.73660488 6.98709344 2.40871186 PANX1 9.39621944 9.71748794 8.9616812 11.3913779 DEFB124 0 0 0 0 TNFAIP8L2 1.51096192 1.15704371 2.7803101 9.87967514 PRKDC 13.2417449 13.679744 14.2825542 12.8527811 SUGT1 10.8754268 11.4033476 11.0885299 10.6708775 PRKCG 1.51096192 1.15704371 3.8509994 3.94204526 NLRC5 8.91004304 8.71073757 5.45252955 9.89716478 CSF1R 4.89384756 3.4409522 1.81557543 12.7013606 APOBEC3D 0 1.15704371 5.17951105 2.40871186 SERINC5 6.73674016 6.94333532 6.79337571 7.14771372 ATRIP 7.61191007 8.31233844 8.10527998 6.66633054 SIGLEC15 2.71369582 3.07038933 1.422233 5.6395216 POLR3G 7.02036885 7.67553369 9.33784487 6.42240122 IL27 0 1.15704371 0 2.40871186 MAP3K5 6.36719631 9.18115226 8.43408607 10.3036552 MIF 2.23572706 0 2.12432814 1.95233357 OTUD5 9.74990294 9.21147465 9.50710087 9.29987196 TRIM14 6.41498114 8.04237074 8.21529031 7.07274895 ADAR 12.0362011 12.0329687 12.4456486 13.1433976 PCBP2 9.58560105 9.79762911 10.7721743 8.84784036 APOBEC3B 5.64731451 6.69125498 6.05419729 3.03210084 DDX3X 13.0981851 13.2568603 13.2517457 13.2024223 DDX41 9.29980329 9.48904513 9.31901723 10.4277214 PRSS3 0.94860085 6.42760617 0 3.03210084 SRMS 0 2.23266076 0 3.80012335 APCS 0 0 0 0 ADCY2 0 0 1.422233 4.07038933 POLR3H 9.5733821 9.62590971 9.89689242 9.1103528 DEFB105A #N/A #N/A #N/A #N/A DEFB106A #N/A #N/A #N/A #N/A POLR3D 10.2445779 9.76324557 9.66008506 10.4216862 DEFB119 #N/A #N/A #N/A #N/A CYLD 10.9737763 10.9876122 9.4751457 10.4441763 DEFB121 #N/A #N/A #N/A #N/A MRE11A 9.16188768 9.25580756 9.95781305 8.20011392 TRIM13 9.27628728 9.45649816 8.87408995 11.5155126 PRKAR2A 10.7120799 11.2119065 11.3281925 11.4444041 TYK2 10.2088806 10.0600609 9.53675231 11.3226324 ART1 0 0 1.422233 2.7548875 AKIRIN2 8.15739747 8.24355484 8.5992434 9.51910546 GPER1 7.19475685 7.32237887 5.33771109 5.75915583 CSF1 9.12166302 8.65004648 6.15946773 10.2157514 DEFB135 0 0 0.87970577 0 REL 6.91348784 6.70832521 7.88746435 8.46352437 DEFB104A #N/A #N/A #N/A #N/A POLR3C 9.29342567 9.05305702 9.04884103 10.6503876 DEFB134 0 0 2.37851162 0 ZC3HAV1 10.644361 10.9539345 10.6380738 10.4707097 SSC5D 6.13975598 6.50795317 0.87970577 3.94204526 POLR3B 8.87061131 9.23232498 9.75139342 7.51932174 POLR1C 8.93484081 8.34549396 9.40008958 9.92728908 CAPZA1 12.8553201 12.8985315 12.0395668 14.2505716 PRKAR2B 7.69807954 9.05975004 8.67525139 5.83364913 TRIM10 0 1.79493566 0.87970577 0 PML 7.87369018 8.58202905 7.55550943 7.27360913 SFTPD 0 0 1.81557543 3.94204526 CASP1 4.21800615 6.62073302 0 7.71945728 SERINC3 11.7797768 12.2324509 10.3737026 11.9367852 POLR3A 9.46593366 9.92018907 10.7749435 9.47609811 VNN1 0.94860085 0 0 0 STYK1 3.98458935 6.56544486 3.35473424 0 PDE1C 10.8732903 10.7857794 5.17951105 3.46727948 DEFB106B #N/A #N/A #N/A #N/A KLRG1 0 1.15704371 5.45252955 3.03210084 PSTPIP1 2.49313492 2.23266076 0.87970577 7.28697353 CLEC5A 0 0 1.81557543 7.44989147 CTNNB1 13.2883297 13.1792093 13.1474069 14.4612383 ADCY4 0.94860085 5.8509994 2.12432814 4.58436125 POLR2H 10.0961353 9.21147465 9.66902677 9.60145511 S100A8 0 0 0 7.62811741 POLR3GL 7.54187101 7.63139535 7.48968743 9.1141067 SIKE1 10.2066115 9.84481559 11.2140944 10.9222796 CHID1 9.65026194 9.63711389 9.21897486 9.54154194 ADRBK1 10.1311239 9.79762911 9.93943229 11.158231 ABL2 11.7318366 12.3580495 10.0991637 11.6020725 KRT16 0.94860085 3.2675358 1.422233 3.03210084 DHX36 10.0286106 10.2266891 9.91956355 9.75087444 SAA1 0 2.23266076 0 0 TXNIP 7.43771047 9.4590217 8.01925712 11.7502213 DEFB133 #N/A #N/A #N/A #N/A DEFB105B #N/A #N/A #N/A #N/A MATK 0 2.23266076 6.67990229 12.036366 TRIM4 8.5415613 9.3731044 8.47208155 8.90517638 MSRB1 7.76725753 7.44997399 7.55550943 7.27360913 NCR2 0 0 0 0 CD1D 0 0 3.76447355 8.14261766 POLR1D 9.23914501 9.52569698 9.90196803 9.95887167 FBXO9 9.7775841 9.62590971 9.80650129 10.1911333 ADCY6 9.23914501 9.80162753 8.75027152 9.29987196 POLR3K 8.07553263 8.27262979 9.07151599 7.71945728 SRPK1 11.209959 11.1356836 12.1984205 10.7762768 ECSIT 9.13121391 7.80051168 9.11800665 8.61393677 ADCY9 8.84467438 10.0897418 9.20261362 9.07620099 DHX9 12.8248693 12.5476489 13.1524687 12.1506422 ANKRD17 10.669204 11.5978151 11.7991966 11.0183393 TAX1BP1 11.613085 11.8537696 10.5894077 11.8126346 APOBEC3G 1.91838623 4.81403765 3.93168306 8.09032418 APOBEC3F 3.89724043 5.46434153 5.36737107 5.14893411 XIAP 10.7072901 10.9130016 10.0825083 11.4533015 MMP2 10.4187697 13.3077444 5.60969587 7.96318509 COCH 4.53853816 2.23266076 9.55134298 2.40871186 GBP5 3.98458935 0 0 1.28688115 PLSCR1 8.98056804 8.49105138 8.32503556 9.00537192 AICDA 0 0 0 0 EXOSC6 10.152437 9.58016433 9.26886945 8.86127305 EXOSC3 9.19421513 8.81711157 8.5992434 9.53595573 RNF168 10.5565348 9.7652861 9.29029538 8.75975506 RNF8 8.89890365 8.89017306 9.66753737 9.56086777 MSH6 11.0782642 11.3755011 12.0848582 9.22564127 NBN 10.6384993 11.0476693 10.9680043 11.3411296 ERCC1 9.99756057 9.6811154 8.65438542 11.5967255 LIG4 8.83003978 9.15643707 8.53543092 10.2501918 SWAP70 10.6096959 10.6148203 9.07376669 10.3199543 APLF 7.72996056 6.74200621 6.33467553 7.04154965 SUPT6H 10.0438885 11.2364388 11.3876889 10.9434818 MYB 4.84799691 5.04701482 5.45252955 5.36562256 SOCS5 8.82416321 12.1102353 8.30222765 8.48103248 HLX 5.82273015 7.54828248 6.81506302 10.2416615 PRKCZ 1.91838623 4.19061486 7.63074036 5.14893411 RARA 6.08172309 7.62234472 7.37033868 8.20716078 DRD2 1.51096192 0 2.12432814 3.26603689 NMI 7.35851934 6.22843392 5.14567746 9.17990909 MUL1 9.57161993 9.40230862 9.13962809 9.01343434 TRAFD1 9.62170392 9.15017885 9.66604643 9.61474665 UNG 10.1711017 9.84095097 10.9558606 8.34100726 PAXIP1 8.23931211 7.58578881 9.31331389 7.21897486 PHB 10.4477858 10.4991383 11.4556406 10.5925038 IGF2 0.94860085 7.15775114 0 3.80012335 SLAMF6 0 0 0 2.40871186 STAT5B 8.96993328 9.49890903 9.26495859 9.9692426 LAG3 3.0721058 1.15704371 2.592158 0 SLC25A6 #N/A #N/A #N/A #N/A CLCF1 8.14801892 7.96613049 1.422233 6.66633054 THOC1 9.17814195 8.92350577 9.40724652 8.40356598 WHSC1 11.2788385 12.080974 11.9172005 9.36104455 TBX21 0.94860085 0 2.94673086 6.21470767 KIR3DL2 0 0 0 1.28688115 OSCAR 1.51096192 1.79493566 1.422233 5.83364913 KLRB1 1.51096192 0 3.23112516 1.95233357 CD300LG 1.51096192 0 1.422233 0 CD300LF 0 0 0 4.66789213 KIR2DL2 #N/A #N/A #N/A #N/A SH2B2 4.35473424 3.2675358 5.14567746 6.49313492 SELL 0.94860085 0 2.12432814 0 CDH1 1.91838623 1.15704371 5.85947267 0 KIR2DL4 0 0 0 3.26603689 TREML4 0 0 0 0 CLEC2B 0 5.58044702 1.422233 1.28688115 COL2A1 1.91838623 1.15704371 10.3226267 3.03210084 FKBP1A 9.71054817 11.0718377 10.1123352 9.90800225 LAIR2 0 0 0.87970577 0 CLEC2D 4.35473424 5.15055968 5.97933945 6.62497818 CD81 10.9077995 11.648007 10.2299003 12.0348849 CD200 0.94860085 0 0 0 SIGLEC9 0 0 0.87970577 7.79610452 CD300C 0 0 0 8.73562372 CD3E 1.51096192 1.79493566 0.87970577 1.28688115 TREML2 0 0 0.87970577 1.95233357 HCST 1.91838623 2.83995959 1.422233 7.84197312 ITGA4 9.71692232 11.4409418 6.67990229 10.4426947 CD200R1 0.94860085 1.15704371 1.81557543 1.28688115 CXADR 8.76394266 3.86393845 10.2618011 8.50973542 VCAM1 10.0665198 0 0 3.46727948 KLRF1 0 0 0 1.95233357 ITGB1 14.7654684 15.5119416 11.4365502 14.0544992 CD300LD #N/A #N/A #N/A #N/A KLRC1 0 0 0 1.28688115 CD3D 0 0 0 0 SPPL2B 9.07780377 8.59589149 7.61227877 8.40356598 ITGB7 4.21800615 3.59693514 4.56437817 12.855581 NCR3LG1 7.23083705 8.12747852 9.69991942 6.92706681 SPPL2A 10.4649133 10.4208445 8.81886973 11.4324532 ICAM4 #N/A #N/A #N/A #N/A JAML #N/A #N/A #N/A #N/A SIGLEC7 0 0 0 4.58436125 CD160 3.98458935 4.09000653 3.93168306 4.58436125 COL3A1 5.41616417 14.6703055 6.94848404 2.40871186 CD33 1.51096192 0 1.422233 8.65563805 COL1A2 16.8202651 16.8390953 0 1.28688115 COL1A1 15.0282778 15.4184486 7.31822644 4.89384756 CD34 1.91838623 3.2675358 1.422233 1.28688115 COL17A1 4.48026512 4.28466219 2.592158 1.95233357 FCRLB 4.84799691 6.46825747 3.8509994 5.31433399 AMBP 0 1.15704371 1.422233 0 IFNL4 0 1.15704371 0 0 SPG21 10.004094 9.73638502 9.26692706 11.6395849 BCAR1 10.9223465 11.1623158 9.32091334 9.56635853 RFTN2 4.84799691 3.86393845 4.51222689 1.28688115 THY1 10.8846513 12.4720181 2.592158 0 RLTPR 5.72519582 3.73660488 7.02480723 4.7473874 PDE4D 8.18982456 8.42012866 8.44799238 7.65921102 RP4-583P15.14 #N/A #N/A #N/A #N/A THEMIS2 5.50716035 4.19061486 6.55673595 9.73393049 CACNB4 3.98458935 2.83995959 7.74799153 9.39529849 STK11 10.7303003 10.0583977 9.92456016 10.1461104 VASP 11.59418 11.5493756 8.50243404 13.6845032 RBCK1 9.10959563 9.64380209 8.18651046 9.44966454 STOML2 11.1340605 10.4880309 10.8205061 10.5749435 RNF31 7.71094416 7.99429686 7.19140473 8.19308177 RP4-583P15.15 0 1.79493566 1.422233 0 PDE4B 7.87369018 9.1842059 5.14567746 6.56056212 PTPRJ 10.2268336 8.76081973 7.66689858 11.1242764 CACNB3 8.51625158 8.43562859 6.49089098 5.20633065 SPPL3 7.95675366 8.24939793 8.54194843 7.7772882 ENAH 12.7694577 12.2478919 12.7593868 8.06732679 CD38 0.94860085 0 0 4.49505553 MNDA 0 0 0 6.12845838 NFAM1 1.51096192 0 1.81557543 6.53838296 PLEKHA1 9.73271014 9.73430317 9.73301532 3.03210084 GCSAML 0 0 0 0 GCSAM 4.98093927 4.99186193 5.00225245 0 CACNA1F 0 0 0.87970577 2.7548875 LPXN 7.16711703 9.70901487 4.70984202 11.3226324 FCRL5 0 0 1.81557543 2.7548875 PAWR 11.5556149 11.0980387 10.9878111 4.66789213 PTPN2 9.00938077 8.63669712 8.6453342 9.44373096 UBASH3A 0 0 0 1.95233357 PRNP 11.5529476 13.1162969 8.60236483 8.76927586 ELF1 8.82119998 9.16576123 8.86114896 10.8008837 PHPT1 9.5432252 9.28745844 8.27122956 10.0863618 EZR 12.4785067 12.2500852 11.0439295 10.7691684 GBP1 10.7498359 9.71748794 1.422233 6.74577515 BTNL2 0 1.15704371 0 0 STAP1 0 0 0.87970577 2.40871186 SLC39A10 10.0438885 10.6910456 10.1361965 11.068429 CMTM3 8.55228484 8.28406063 8.36233838 10.3344744 PRKCH 2.90496572 3.4409522 7.93274625 7.98788928 TESPA1 0.94860085 0 0 1.28688115 KCNN4 7.23964626 2.83995959 0 12.6819346 RPS19 13.0512293 13.2091959 12.9715364 12.9115324 INS 0 1.79493566 0 0 PARP9 7.54187101 7.43978934 7.57470705 9.18348651 SOCS3 8.91004304 9.91282947 5.17951105 9.13637598 IFNGR2 9.79122802 9.64158215 8.57723998 12.7119014 PTPN1 10.5583155 10.3827213 9.99861864 10.9455828 IRF9 3.80426012 2.56803211 3.09592442 4.7473874 IRF6 1.91838623 2.56803211 4.66277517 1.95233357 IFNGR1 10.3961338 10.0550519 9.16093027 11.5267975 STAT1 10.5323657 11.6290378 9.89179889 10.8822074 IFI30 0.94860085 0 0.87970577 6.64573048 TRIM38 6.6727082 8.63223186 7.06156021 9.55261147 IRF2 7.32553033 7.70141044 7.05245937 9.7676217 MID1 9.79574747 9.62366205 11.8307766 0 MT2A 11.234584 12.3181982 7.08841725 6.68664059 IRF5 3.22342255 1.79493566 2.94673086 9.69446236 SUMO1 11.1316769 10.6693634 10.9024731 10.7997268 TRIM68 7.74247787 7.78443855 7.21606678 5.55397481 CD44 12.9800378 13.8973879 5.00225245 12.3162702 TRIM34 2.23572706 2.83995959 0 1.95233357 SOCS1 5.25058267 4.19061486 2.592158 4.7473874 PIAS1 8.45277662 8.6676438 8.63012148 8.77873424 CDC37 12.2248187 12.0072726 11.5466678 12.7272674 MED1 9.58560105 10.3089192 10.9943534 10.1015293 NR1H2 10.4089772 9.94205993 7.41362793 10.2771711 MX2 5.93640238 3.73660488 1.422233 5.55397481 XAF1 0.94860085 6.79103262 0 7.78672704 IFNAR2 6.78607355 6.15542543 5.77346893 8.27565895 IP6K2 9.83140226 9.16884759 9.04196025 9.83271599 USP18 3.98458935 6.56544486 8.41645977 7.27360913 IFIT3 9.00419237 8.9050861 3.67242534 9.4257614 IFIT1 7.04078287 9.19942697 6.97750891 8.02818235 IFIT2 7.04078287 8.10181813 2.7803101 7.00977264 RNASEL 7.02036885 7.61331064 7.04330075 9.09148828 ISG20 3.0721058 3.98185265 3.67242534 7.64896869 EGR1 5.79908731 6.18010807 2.94673086 8.83428142 STAT2 10.0875557 10.5174529 8.69289443 9.9836492 IFI35 6.41498114 5.88141991 5.36737107 9.59342847 IFNAR1 10.5864082 10.5403315 9.47002838 11.8746664 UBE2K 9.33127527 10.3693356 11.393546 9.66922169 GPRC5B 8.39835892 3.4409522 7.74234312 0 FOXP1 10.1641276 10.1220256 9.77783063 8.20716078 RC3H2 11.7986662 11.3340665 11.074563 10.5694949 ERBB2IP 12.9129717 12.8598104 11.0924136 12.7821485 HSPA1B 9.78971295 8.31233844 13.2523653 9.5961152 HSPA1A 9.67664471 8.70649602 13.5537733 7.41388175 AIF1 1.51096192 0 0.87970577 8.67097485 ASS1 10.7904137 9.50870595 7.31061278 10.7950656 GAPDH 14.4926563 14.71874 13.8579723 14.3363399 EPRS 13.1818573 12.664045 12.5053749 12.6885432 DAPK3 10.7820891 10.645127 9.54324453 10.0787112 MRC1 0 0 0.87970577 1.95233357 SYNCRIP 12.0707985 12.3017334 12.2904653 11.5055684 AQP4 0.94860085 0 4.51222689 3.46727948 SLC26A6 8.51258246 8.56334883 8.32129678 10.4692552 RPL13A 13.3363029 13.4659298 12.6257568 13.446432 EDN1 7.1004521 9.45649816 4.84247606 5.02724254 STAR 0.94860085 2.23266076 1.81557543 1.95233357 DAPK1 10.3911684 7.10706011 9.53184929 10.3488499 CD58 8.59786633 6.74200621 6.30451104 9.9567827 TDGF1 0 0 0 0 RORA 1.51096192 7.42944859 7.9227925 1.28688115 LY9 0 1.15704371 0 3.03210084 USP17L2 0.94860085 0 1.81557543 0 PUM1 10.9664406 10.7187469 11.0678108 10.4924541 PUM2 9.37623394 10.8166797 10.5767772 10.219229 VAMP8 1.91838623 2.83995959 6.86777294 11.04801 SNX4 9.97780939 9.2788908 9.66008506 10.3134613 BAX 9.5663395 9.99007559 9.19024446 9.7192519

TABLE 4 Differentially expressed genes in mock vs ZIKV treated cells, Related to FIG. 13A. gene_name CHME BJ 293FT THP1 PRKDC 0.55856801 #N/A −0.5171828 0.5678045 ATP5J2 0.03250525 #N/A 0.12618779 −0.7223692 CUX1 0.33250463 #N/A −0.7744567 0.59583179 KIAA0754 0.69031731 #N/A −0.4817685 0.70147337 SHANK3 0.1325234 #N/A −0.1932178 0.67542576 ZBED6 0.23744485 #N/A −0.1458937 0.65822503 PEG10 0.38703256 #N/A 0.05514638 3.34969884 RPL36A −0.5163688 #N/A 0.71993133 0.33299626 SMIM20 0.11472651 #N/A −0.0788868 −0.6510827 ITGB3 −0.4062701 #N/A 1.07866076 0.35009084 TMEM141 −0.2728154 #N/A −0.0280894 −0.6319133 ETV5 −0.4302263 #N/A 0.68421692 0.50675169 PCDHGA11 −0.7805866 #N/A −0.4143672 0.70705975 HIST1H3F −0.1981391 #N/A 0.01109358 −0.6276276 OAS1 −1.1541368 9.58142668 5.3096096 0.90513148 NPY 5.9728042 3.48888859 3.73845785 −8.6155662 PRDM16 −2.1052731 0.02462381 −0.3462215 −8.6155662 LPAR2 −0.3416272 7.92084439 −0.0173286 0.9173359 KRT80 0.5004813 −0.0203586 5.30202839 −6.7410313 MXRA5 2.84875627 −0.6585835 −1.8433505 −6.7410313 PSMB8 −0.0257905 0.43896737 6.72832517 −0.4983962 GIPC3 3.59074958 6.44630765 −0.4725947 0.86615677 MATK 6.40679881 −0.9016165 −0.1026186 −0.2989202 LYZ 6.3945123 3.4332996 −0.0464664 −0.5886975 OAS2 0.63106751 3.81151293 −6.385417 1.12260925 LAPTM5 −0.4429111 0.1635659 −6.385417 0.41452932 MMP1 −0.1052119 −0.1527386 −6.385417 −0.4904597 DKK1 −0.2418678 0.15045916 0.28262609 6.37288581 WAS 1.10196892 6.06626917 6.30963839 0.69193795 NUP210 6.22554827 0.25025596 −0.2636351 0.56760781 SSTR1 0.63948628 −0.4193241 −1.0261776 −6.1560313 COL4A5 0.42751738 −0.1978899 −0.045773 −6.1560313 IL1RN 0.66167517 −6.067605 −4.8004512 0.50176743 DOCK2 0.27488063 −0.0610358 6.04365971 0.45958114 SPI1 −5.9015357 3.4332996 −5.8004174 0.38688844 CD52 −1.1724122 3.4332996 −5.8004174 −0.7118497 MX2 0.58615835 3.668701 −5.8004174 1.60389444 ITGAM −2.169796 3.48888859 −5.8004174 0.37023318 KRT7 −0.1314643 0.21904008 −5.8004174 5.38519517 C5AR2 −0.9400716 5.78928385 3.73845785 −0.2420397 UNC5C −0.5846658 5.4613723 −0.5331489 1.46334881 CACNA1C −0.0046296 −0.5821937 −0.8378071 5.36040653 CD163 −2.1687748 4.43069973 5.32430546 0.58211974 VCAM1 −0.6958874 3.48888859 5.30202839 −2.1887125 PRTN3 −1.1021635 3.48888859 5.30202839 0.57108024 CLEC11A 5.22547271 0.35352936 0.16020668 −0.2368824 ALDH7A1 0.33541349 −0.6986587 −0.4720292 −5.1560457 LUM −0.321423 0.00161738 0.18579467 −5.1560457 HRH3 −4.9015622 −1.3299475 0.28799462 −5.1021092 ADCY8 −0.5636555 5.07649491 3.71793484 0.52645495 MERTK −2.7511542 5.07649491 −0.1266408 0.43068354 PIK3R5 −0.7306224 −5.0676274 −0.1116798 0.38149518 LCP2 −4.9015622 −5.0676274 −1.035987 0.47272564 NOVA1 0.22588338 −5.0676274 −1.1821583 −3.4084252 RBM20 4.58739662 −5.0676274 −0.6143299 −2.7134571 HCN4 −0.3044137 −5.0676274 −0.1952518 −4.0920678 ELMO1 −4.9015622 5.05623944 0.19035631 0.89102265 LINGO1 −1.1367624 5.05623944 −0.8259569 0.26520487 PPAP2B 0.50024667 −0.2495042 0.10833637 4.96601755 LRRN1 0.50223481 −1.8622136 4.73927048 4.94952467 ID4 −0.0410974 0.07143908 0.2720259 4.94952467 MIDI 0.31719771 0.13354129 −0.1175922 4.93228693 RUNX1T1 −4.9015622 −0.7329959 −1.1621057 −2.3915117 PCDH19 −4.9015622 0.10850427 −0.8945431 4.37278862 ASB18 −4.9015622 −0.2890079 −2.8460059 0.19350137 MMP19 −0.203705 −0.0882791 −4.8004512 0.62125278 TNFRSF1B −0.4218794 0.27427814 −4.8004512 0.29266972 IL7R 0.39151831 −0.0430196 −4.8004512 0.15542917 SLC43A3 −0.1352096 −0.0764032 −4.8004512 0.34169585 SEMA6D 4.58739662 0.07908043 −0.0674083 0.92417597 LST1 4.58739662 4.43069973 0.55958861 −0.8234998 CNR1 −0.5056187 4.49134188 0.40180746 0.59870044 SLCO5A1 −0.3259786 −0.4013902 −0.3957229 −4.4049425 ACTA2 −0.6319022 0.23195277 −1.4478652 4.3976275 GFRA1 0.43716748 0.29025356 −0.2804988 4.3976275 THY1 −0.2593801 0.19149247 −1.6163056 4.37278862 ARL10 −0.0806352 −0.1264517 −1.3374969 4.37278862 EMX1 3.66367464 0.29143604 0.83321132 −4.2848041 ZFHX4 0.31941866 −0.281322 −1.1811921 −4.2126614 MX1 1.13932495 4.20656455 0.35482213 1.10676095 CREB5 0.15233725 −0.0121701 −0.6610423 −4.106626 SYNGR3 0.04624613 1.09678061 0.27369681 −4.0920678 SDK2 −0.515328 −0.5422419 −0.7294643 −3.9619542 CHI3L1 −1.022842 −0.589369 3.73845785 0.40325958 IL24 −0.0427296 −1.3117922 3.73845785 −0.4118264 SEMA5A 0.46474002 −0.2663807 3.73845785 0.94484013 NCF4 3.59074958 3.4332996 3.73845785 −0.503469 RAMP1 −0.1123147 0.60674164 3.73845785 −0.5679737 COL1A2 0.20670315 0.00303122 3.71793484 0.1691995 PIK3CG −0.1367247 3.4332996 3.71793484 0.38469389 SH3BP4 0.23393648 −0.0600997 −0.3223726 −3.697865 PROX1 3.66367464 −0.9511435 −0.7272002 0.60853134 MLXIPL 3.59074958 1.00141192 −0.1497451 0.82336116 CRIPAK 3.57571573 −1.890997 −1.1982972 0.18550482 HOPX −1.2135108 3.48888859 −0.4928824 −1.0797892 BTK 1.20778658 3.4332996 −0.1421229 −0.4641776 MSR1 −0.3675987 3.4332996 0.96923679 −0.3189994 MAMDC2 −0.09718 0.63440714 −1.6840843 3.39560669 CNN1 0.14887662 0.328907 0.62863108 3.39560669 XIRP1 0.88192383 −1.7266461 −3.350767 0.95095787 LMOD1 −0.5227811 0.4424635 −0.4400164 3.34969884 KIF5C −0.2096428 0.61973636 −0.0581768 −3.327976 CYP46A1 1.53634708 1.68969137 0.37109241 −3.176782 KIF21B 0.03336338 3.15919917 0.06643995 0.51426548 LPHN3 0.66870543 −2.865779 −0.10518 0.24998614 IL8 −0.195687 −0.5106556 −2.8433506 −0.7594216 AUTS2 0.2345527 −1.0777958 −1.0442454 −2.7870897 CTD- −0.1799742 −1.7355251 −1.3830569 −2.7838653 3088G3.8 DIP2C 0.34259199 −0.033156 −0.0165371 −2.69401 MT-ND6 0.10501022 0.78976666 2.66993642 −1.6975222 FLNC 0.68010938 −0.1862298 −0.019039 −2.393736 IGSF9B −0.6255443 −0.6109856 −0.8907965 −2.3705094 ACAP1 −0.3346675 −0.2731026 0.46329324 −2.3439557 SLC1A3 0.02634705 2.29186556 −0.0390104 0.27651271 CCDC88C 1.64303969 −2.2909711 −0.1159312 0.42054278 NCKAP1L −1.8845369 −0.3029683 2.28806291 0.31893842 STU 0.05887474 −2.2787969 −0.5491355 0.33799939 IFIH1 0.08893951 2.25581554 −0.1415286 0.49912749 TERT 0.37596158 −0.3317167 0.06170395 −2.252293 GYPC −2.1687748 0.18068601 0.05783795 −0.3746608 MMP9 −2.1272702 1.26233647 −0.7120835 0.28539908 TUBB4A −0.5477682 −0.3317167 −1.6115098 −2.1217145 THBD −2.0855064 −0.7273101 −0.2533527 0.46792244 MT-CYB −0.1903529 0.48389271 2.0707826 −1.0098223 IFIT1 0.73373208 2.05464698 −0.0606624 0.73885966 GPRC5A 0.38137344 −0.0572162 −0.6374925 −2.0465405 EVI2A 0.54548126 0.43280834 −2.0404567 −0.6103066 EPPK1 2.02470531 −1.1137453 −0.6468634 −1.2439358 EGR2 2.02043905 0.02466681 −0.1891361 0.42731675 MT-ND5 0.08356319 0.56786435 2.01919912 −1.162643 PRKCD 1.2211035 −1.991135 −0.8944593 0.41397933 MDK −0.1001546 −0.0524536 −0.109649 1.98957322 COMP −0.1367109 −1.2619042 −1.0392533 −1.9764558 MT-ATP8 0.0818921 0.71675793 1.96964005 −1.837835 ILDR2 0.58175194 0.68246955 −0.2755375 −1.9660671 FOSL1 0.10405813 −0.0220373 1.96399611 0.76615599 GAS7 −1.9441854 −0.044558 −0.1643115 0.30183955 POLR2A 0.16205426 −0.2040257 −1.8721099 0.40085782 MT-ND1 −0.1745864 0.77002376 1.8135832 −1.2644244 COL5A1 0.20319389 −0.0099103 −0.1728984 −1.799472 KMT2D 0.21193923 −0.5173759 −1.791409 0.37477863 CASP4 −0.582906 0.02620174 1.77288201 −0.4271332 GPRIN3 −1.7557724 0.39971002 −0.461149 0.73153932 VAMP8 −1.7557724 −0.2859506 −0.1387797 −0.6752804 ZNF385A 0.13253733 1.57153385 −1.7531018 0.55200081 WNK2 −1.7217701 0.28519585 −0.7243857 −0.5807958 GLI3 0.61838097 −0.2275776 −1.2886567 1.69744465 REXO1L1 0.30180717 0.43750793 −1.6925744 −1.6966166 PLEKHH1 −0.6089734 −0.648367 −0.1653834 1.68163149 MT-ND4 −0.1118824 0.42706104 1.66095625 −0.8697342 RMI1 −0.0847928 −1.0028894 −1.6287174 −0.687812 SLIT2 −0.2163053 −0.3665019 −0.5662179 1.61161863 PARP9 0.464091 1.60496377 −0.1841645 0.56527382 RAPH1 −0.021561 −0.0524204 −1.5888207 −0.2970959 FUS 0.33108673 −1.5808059 −0.3294648 −0.0545556 A2M −1.5784032 −0.1397512 −1.3287134 0.32472385 MT-CO2 −0.3970466 0.27714226 1.57779709 −0.4191846 OLFML2B −0.2362135 −0.1238046 0.3111769 1.56808491 SMG7 0.45614341 −1.0275234 −1.5534647 0.29014321 TNFSF15 −1.1719671 1.53428229 −0.6259549 0.44739545 ALPK3 −0.118396 1.52534352 −1.1010232 0.60929055 IL4I1 −0.3675987 −0.2936225 −1.5195513 0.35301686 FRAS1 0.2818312 −0.4792134 −0.7574238 −1.5157248 PCLO 1.40523564 −0.225452 −1.4921478 0.87746628 SDHC 0.12989616 −1.4812605 −0.5428579 −0.1694983 SLCO3A1 0.25499804 −1.4713173 −0.63527 −0.2624378 C3 −0.0454665 −0.3404185 −1.4574456 0.45247309 PLBD2 −0.1682737 0.22232424 −1.4517393 0.24813893 SMARCD3 −0.0965059 0.19877868 0.21943459 −1.4414646 MT-ATP6 −0.2520609 0.2168809 1.43728376 −0.6207972 SRCAP 0.17784799 −0.3278129 −1.430524 0.41888201 SORL1 −1.4237604 −0.0662354 −0.4453764 0.21578459 MT-ND4L −0.0744306 0.72292561 1.42143397 −1.0814801 DSP 0.00362152 −0.1222561 −0.3700848 1.41934258 C1orf226 −0.8219199 0.16983364 −1.4177899 0.0694358 ONECUT2 0.84433511 −0.3151689 −0.9857611 1.39786017 EP400 0.50858744 −0.8116141 −1.3965709 0.80082717 CFD −0.5700285 1.39524113 0.27054919 −0.6135203 RERE −0.0374192 −0.398216 −1.3942566 −0.1021657 CYFIP2 −0.5871374 0.04913455 −0.4701895 −1.3914874 QDPR 0.23043737 −1.3900388 −0.640424 −0.5224256 ADAM12 0.27546743 −0.0226244 −0.1796894 −1.3842479 IGF2BP1 −0.1407351 −0.2648655 −0.5942332 −1.3842479 MT-ND2 −0.2423961 0.56063061 1.3806633 −1.3224996 NOVA2 0.0804315 −1.3299475 −1.1529025 −1.3692276 RHPN1 1.36635457 −0.8293821 0.71566425 0.10830908 PLCG2 −1.3644571 −0.6584898 −0.4526192 0.56848258 STX16 0.11789007 −1.2712963 −1.345218 −0.0586111 ATN1 0.13059953 −0.3258559 −1.1490467 1.33363436 COL12A1 0.5439358 −0.2276631 −0.5238261 1.32635874 MBD6 0.12842861 −0.305501 −1.1072236 1.31939386 FILIP1L −0.0115303 0.02802335 −1.3052451 0.70583022 CSF1R 0.11756287 −1.3029882 0.69886113 0.53882988 ABCC3 −0.2206392 −0.1372932 −1.3009373 0.42875484 KDM6B 0.31010062 −0.5881058 −1.2971445 0.40586579 ZFHX3 0.13343599 −0.4458125 −1.2888444 0.09676354 RFX7 0.34253599 −0.2184657 −1.286543 0.70147993 ATF7 −0.1561397 −0.531292 −1.2850829 0.90567832 CTSH −1.2793388 0.36311133 −0.2898567 −0.3039583 VAV3 −1.1671817 1.27225733 0.01844571 0.25766211 PHF16 0.03366559 −0.4136876 −0.4699743 1.26745174 KIAA1199 −0.4592599 −0.3373217 −1.262705 0.43347718 CHERP 0.34595099 −0.5713322 −0.7094687 1.26085851 USP14 0.3756032 −0.7925867 −1.245602 0.0790873 LGALS9 −0.1742321 0.82372476 −1.2327962 0.44460882 KIF20A 0.16385481 0.2421316 0.06779917 1.23205536 TOP1 0.31373711 −0.5496323 −1.2301152 −0.0696299 POM121C 0.38114235 −0.3506261 −1.2284191 0.43954652 ARMCX4 0.30956809 −1.227344 −0.7015578 0.70017075 NFIC 0.37044793 −0.4279061 −1.2252027 −0.0411676 NEIL3 0.12741199 0.04325957 0.07042456 −1.2233172 UCP2 −0.0663055 −0.0269073 −0.8780106 1.21644916 MT-CO1 −0.3729258 0.40780064 1.21150156 0.5683562 FCER1G −1.2008899 −0.5715409 −0.0464664 0.3191262 TMEM56 0.39382906 0.5776071 −0.1787177 −1.1932676 42616 1.1928605 −0.1680268 −0.5904962 −0.1724611 CIT 0.29451654 −0.1200916 −0.2221024 1.19055104 SPEN 0.32643477 −0.3938108 −1.1884296 0.75326 EIF4E3 1.18017908 −0.3720995 −0.7396968 0.04360486 EVI2B 1.1798008 0.05193235 −0.8178706 0.8387684 TCF7L2 0.31021404 0.06709651 −1.1764611 0.01715123 SRRM2 0.34610083 −0.7069288 −1.173218 0.75927743 WDFY4 −1.1730145 −0.708919 −1.0459601 0.57420167 PIK3CB 0.12421695 −0.4666868 −1.1727642 0.0693577 DOCK8 −1.1727419 −0.881099 −0.4861799 0.61320715 ARID1A 0.44436448 −0.382666 −1.1676271 0.77124323 MT-CO3 −0.4835282 0.33258417 1.16501721 0.29632562 CD14 −0.2255508 1.1618252 −0.0394213 0.39682377 CCNK −0.0803625 −0.2435617 −1.1615384 −0.0180263 SON 0.2930706 −0.723822 −1.1568301 0.47072176 FAM65A 0.02114799 0.10674684 −1.153156 0.57175245 RUNX2 0.26753735 −0.0673458 −1.1509865 0.62001825 NFAT5 0.43966001 −0.3438441 −1.1497174 0.487456 EMR2 −1.1482367 −0.3646666 −0.5344985 0.46457246 LOX −0.0097495 −0.7443344 −1.1457178 −0.0312525 ANP32B 0.14811145 −1.1378669 −0.7758419 −0.1525176 DACH1 −1.1367624 0.29143604 −0.734726 0.87622688 SAMD9L 0.31020835 0.60597837 1.13509854 0.81730475 LRP1 0.61268665 −1.1348502 −0.9422073 0.48383424 MXRA8 0.32984102 0.15374021 0.37564714 −1.1340805 MAP1B 0.5115714 −0.2087157 −0.8254015 1.13346819 GBP1 0.03477046 0.44000044 1.1303804 0.32261185 CCDC88B 1.12953438 0.91736448 −0.0559382 0.49998204 PGF −0.5222585 0.11458045 0.20421268 −1.1259466 WASF1 0.05036229 −0.2231193 −0.13366 1.11911897 ABCA1 0.42721694 0.08687954 −0.4123377 1.11647413 DSG2 0.20236697 1.11575342 −0.6391983 0.66454434 SRGAP1 −0.0349331 −0.3728424 −1.1070133 0.64166275 TRANK1 0.99444151 −0.3991849 −1.1068927 0.69698881 HIC2 0.11527956 −0.2538066 −0.0461373 1.10425129 KIRREL 0.25838526 −0.1205885 −0.1702649 −1.104014 MKI67 0.4867459 −0.3081071 −1.1037905 0.70931992 HIST1H4K −0.2156987 −0.2934607 0.94457425 −1.1018549 EYS 0.37334583 −0.5396395 −1.1018225 0.31710378 NDUFB1 −0.1938241 0.24759739 0.30761455 −1.098758 ZFP36 0.48479605 0.45087036 −0.8839947 1.09444208 RGCC 1.08461982 0.1789841 0.15342221 −0.4831311 TICRR 0.2108576 −0.4013499 −0.3351883 1.0796965 BCORL1 0.29674532 −0.7578045 −1.0621236 1.07842476 QSER1 0.21001806 −0.3012598 −1.0745008 0.28312994 ZNF804A −0.1552824 −0.1641029 −0.1476532 1.07130476 CCDC107 −0.3016173 0.79366283 0.67974971 −1.0712081 TRIM14 0.30554472 0.49553909 −0.3121917 1.06671873 SEPHS2 0.07188116 −1.0654829 −0.2648831 −0.2372006 OAS3 −0.1419907 1.06430862 −0.5552335 0.96237942 HIVEP3 1.06120211 −0.3847046 −0.9928498 0.55795123 DAP 0.03699283 −0.7187563 −1.0611614 0.14920605 EP300 0.22775632 −0.2058586 −1.0605785 0.63766128 HIPK2 0.30973459 −0.625363 −1.0593831 0.77960613 CRYL1 −0.4342605 0.1986127 −0.1967358 −1.0572807 ADNP 0.09764623 −0.3730778 −1.0556177 0.36032707 UBL5 −0.0398895 0.2158329 0.1225837 −1.0554302 LONRF2 0.19257195 −1.0522365 −0.4813123 0.11330967 ZMIZ1 0.39051171 −0.3416421 −1.0463175 0.71269777 PEX7 −0.2555182 0.74870317 0.2318023 −1.0461369 TRIM22 −0.1291734 0.43486453 −1.0458303 0.66443171 HIST1H3C −0.236828 0.09898507 −1.0458303 −0.2756738 DUSP23 −0.5736764 0.07823363 −1.042597 −0.6506835 PML 0.17509999 −0.1606207 −0.1263692 1.0409416 PTGS1 −0.644067 −0.1423909 −1.0392153 0.24579125 PLCD4 0.58829374 −0.3698972 −1.0366483 −0.6118727 MRPL43 0.02434269 0.30720908 0.0673465 −1.0358881 LMLN 0.0584856 −0.2993258 −1.0356128 0.43055772 TPP1 0.25787154 −0.0224647 −1.0352202 0.80260583 HIST1H4D −0.1523439 0.02678756 0.07260453 −1.0338073 BHLHE22 0.84447004 −0.3029683 1.0333753 0.31425891 RAC2 0.35808516 0.50528824 −1.0261776 0.33668025 CDCP1 −0.3434544 −0.6335388 −1.0260552 0.50099988 KMT2A 0.49947188 −0.3113809 −1.0244917 0.9623194 TCIRG1 −0.0568849 0.0708318 1.01924123 0.3686595 FYCO1 0.61438847 −0.997829 −1.018591 0.48093687 NAV1 0.38924411 −0.4341749 −1.0147577 0.16921684 CENPF 0.42862904 0.03319866 −0.1285281 1.01437395 PTPN12 0.13059914 −0.7024465 −1.008294 0.09625941 MAMDC4 −0.0337778 −0.2717828 1.00766345 0.07979122 PEAK1 0.42636878 −0.6044548 −1.0027593 0.06128411 AHNAK2 1.00267349 −0.5150554 −0.7209908 0.80047227 NCOA6 0.59679242 −0.4330229 −1.0003214 0.72866641 PTRHD1 −0.2496686 0.26284598 0.03301546 −0.9999594 IGFBP3 −0.0083693 0.23051347 0.9997056 0.05070075 GSE1 0.3012102 −0.5855585 −0.4458471 0.99851194 HPRT1 −0.0138153 −0.9976442 −0.8006981 −0.2256058 INCENP 0.33677122 −0.0505206 0.02128117 0.99726922 RPRD2 0.21639054 −0.0227392 −0.6406683 0.99383304 PLEKHG2 0.14959398 −0.1803355 −0.3843273 0.99164809 MTUS1 0.9891786 −0.7554818 −0.3079831 0.45861058 ROMO1 −0.075124 0.25388424 0.11375394 −0.9849351 SCAF4 0.23897134 −0.5273573 −0.9839867 0.73519729 ZMYM3 0.1437086 0.11495333 −0.3044171 0.98066388 ZNF32 0.12872572 0.29144493 0.05536028 −0.9779282 HTRA1 −0.2280955 0.14265745 0.11840367 −0.9764346 PRRC2C 0.35071405 −0.1652916 −0.9756104 0.90514103 SGCB 0.12121462 −0.3350771 −0.4887875 0.9748984 PRR12 0.31763133 −0.6850117 −0.9695994 0.69110584 NIPBL 0.33050465 −0.7355763 −0.9680475 0.24550172 HIST1H4C −0.1672742 0.10211209 0.02360819 −0.9672796 PMVK 0.15279751 −0.9665166 0.09814498 −0.308098 MAP2K3 0.08241877 −0.6944746 −0.9601106 0.13790536 LAMTOR4 −0.1491644 0.18264958 0.00561578 −0.9597033 EPHB4 0.30139358 0.06608928 0.05046969 −0.9592366 C21orf67 0.00976938 0.95765745 −0.2309025 0.32537538 ZMIZ2 −0.1680968 0.09659525 −0.289224 0.95741421 RPS18 −0.1046989 0.18103916 0.07115236 −0.9563046 PHACTR4 0.14878318 −0.1290776 −0.4388188 0.95574589 S100A6 −0.0449636 0.17273931 0.9549477 −0.6335333 RUNX3 −0.1285263 −0.9547057 0.05886197 0.39110508 PTP4A1 0.12562581 −0.7162147 −0.9501469 −0.0399866 NSRP1 −0.0840151 0.29114616 0.07523641 0.94934661 CHAMP1 0.2641776 −0.061881 −0.9452495 0.92827972 SEC22A −0.1763303 0.04969652 0.01218869 −0.9443834 RPS10 0.0521097 0.32133216 0.187609 −0.943421 EFNA5 0.09591948 0.28201694 −0.4482544 −0.9404129 ZFP36L1 0.09255463 −0.03629 −0.9375689 0.5600723 TBC1D7 −0.0627878 0.05883048 −0.1853933 −0.9365536 FOS −0.0068944 0.93566798 −0.1515304 0.37993188 ADAMTS5 0.17378947 −0.597037 −0.5808157 −0.9341167 C15orf52 −0.2118316 −0.7227749 0.13276681 −0.9341167 NUDT2 −0.1455226 0.25967918 0.30780043 −0.9323624 CREB3L2 0.10023243 −0.2410613 −0.9314225 0.86276453 SEC63 0.14934785 −0.5354326 −0.9308545 0.13340559 PCBP2 0.04987286 −0.0394607 −0.9306552 −0.0776712 EPB41L1 0.56541984 0.06961527 −0.6064192 0.9253706 RPS3A 0.07163863 0.05682431 0.18214075 −0.9252828 SMNDC1 −0.0692168 −0.5590946 −0.9236545 0.21189466 IFI27L2 −0.0866673 0.05998045 0.28017713 −0.922902 VDR 0.06976031 0.13290143 −0.2664268 0.92196745 PTPN14 0.48205476 −0.4965729 −0.9213774 0.78114055 RPA1 0.30164496 −0.9213504 −0.3120327 −0.0028605 GPC4 −0.1090106 −0.9187263 −0.607676 0.29335569 NAF1 0.30257622 −0.5312605 −0.9157635 0.15843862 GATAD2B 0.43585142 −0.3364681 −0.9139008 0.68869668 C10orf12 0.40408291 −0.2807151 −0.9119921 0.82210224 POLE4 0.04612104 0.14400089 −0.034875 −0.9113613 PROSER1 0.0222151 −0.1515912 −0.9101879 0.58193352 R3HDM1 0.08283854 0.04721923 −0.9094027 0.45148306 STXBP1 0.35663077 −0.4703101 −0.9092918 0.54331046 PIK3CD 0.22892846 −0.0045877 0.1728646 0.908914 KMT2C 0.26336954 −0.3605869 −0.9088592 0.6005487 DISP1 0.01691058 −0.2025554 −0.1646181 0.90633633 MED30 0.08628878 −0.0616118 0.11439065 −0.9018805 CNOT6 0.40970014 −0.6256697 −0.9014494 0.21629706 POP7 −0.1532846 0.08626463 0.11540445 −0.9012932 UQCR11 −0.0467395 0.03333818 0.00254441 −0.8998578 MRPL13 −0.0403306 0.13461203 0.1482989 −0.8977186 AFF1 0.42366746 −0.1274649 −0.6364188 0.89763005 USE1 0.14787306 0.09290884 −0.116306 −0.8972467 MED25 0.17391447 −0.013439 −0.1177897 0.89670523 KCNMA1 0.19664352 −0.5673327 −0.8957927 0.00351517 RNF213 0.59732716 −0.1003189 −0.5463444 0.8936837 MRPL54 −0.0499691 0.43212516 −0.0739844 −0.8929659 NXT1 −0.1251647 0.12862057 0.01323725 −0.8911934 ASAP1 0.25644723 −0.1445016 −0.8900354 0.6159554 MYRF 0.31031317 0.88970737 −0.0754236 0.61639206 SF3A2 0.22604264 −0.0850332 −0.2709879 0.88689089 BRPF3 0.0173829 −0.4066345 −0.6844504 0.88530968 NDUFA13 −0.2701047 0.07319257 0.03117576 −0.8827915 TMEM18 −0.2813936 0.19101209 −0.004335 −0.8783266 MKL2 0.52903668 −0.530769 −0.8780809 0.64455523 NAV2 0.21650514 −0.4126277 −0.7283668 0.87763418 ARHGAP30 −0.5108134 −0.8775704 −0.6567143 0.30119336 EEF1B2 −0.1682227 0.16702852 0.16339712 −0.8773841 PGAP1 0.50218346 −0.6667299 −0.6605524 0.87634831 EHD2 0.13385363 0.00422457 −0.875667 0.70565097 TACC3 0.15016803 −0.4554933 −0.2779966 0.87520113 FBRSL1 0.04290985 −0.2413952 −0.2078766 0.87424255 ZNF704 −0.8737058 −0.4653351 −0.4152791 0.03395607 IGFBP4 0.24317303 −0.8733671 −0.5665169 −0.0502305 IQSEC1 0.39284499 −0.0026487 −0.8714528 0.45861417 SUZ12 0.02440281 −0.7807132 −0.8710514 0.21634094 NPM3 −0.163286 0.3019828 0.12827919 −0.8701307 HSBP1 −0.0627247 0.12124873 0.12726812 −0.869425 CD4 −0.8461443 −0.8693469 0.04531473 0.68015175 BCL3 0.86876902 0.11926206 −0.2072062 0.44149448 FBLN1 0.29137437 −0.4219101 −0.6170268 −0.8677751 FAM122B 0.23907077 −0.3407692 −0.8673955 0.16584691 AFF3 −0.5720862 0.16400536 −0.7618979 −0.8669188 SIVA1 −0.1561811 0.3087107 −0.0712679 −0.8656761 PHF5A −0.1701548 0.11244088 0.13886836 −0.864815 ABL2 0.36216146 −0.2451381 −0.8638198 0.45179241 RSL24D1 −0.2389157 −0.0389964 0.30423202 −0.8637014 PABPC1 0.26519502 −0.6777439 −0.8630539 0.39365829 SKI 0.38623209 −0.324062 −0.8616356 0.46164583 CYP51A1 −0.4211367 −0.3515389 0.16786758 −0.8610433 KDELR3 −0.2800236 0.16643045 −0.0794664 −0.8576793 COX7B −0.0728593 0.02595875 0.12631499 −0.8515755 CREBBP 0.21570396 −0.2994133 −0.8498336 0.50680887 PARP10 −0.0871189 0.84909812 −0.087318 0.39780405 FAM98B 0.19335649 −0.6535028 −0.8463523 0.15103079 PPTC7 0.31887066 −0.648637 −0.8459845 0.12440082 FUOM 0.31517029 −0.1921098 0.18463805 −0.8435553 NCOR2 0.08793661 −0.7958127 −0.8432483 0.27145866 PRADC1 0.02138664 0.32502702 0.15063122 −0.8404689 PDE4A 0.41208157 −0.7789678 −0.8388351 0.71554887 RAB32 −0.0783444 0.1962406 0.18568248 −0.8383766 INO80D 0.61924075 −0.2778023 −0.8366363 0.54465976 SNRPG −0.2083257 0.11393086 0.15297169 −0.8362501 GRIN2D 0.23321949 −0.5385676 −0.8356754 0.64094294 ANPEP 0.04920187 −0.1823364 0.83558492 0.61663112 POU2F1 0.52119873 −0.3031778 −0.8354182 0.58917193 TNC 0.23920999 −0.1158839 −0.1121215 0.83383536 CBFA2T2 0.33570197 −0.8326576 −0.3465489 0.04924959 AAK1 0.1856245 −0.2223762 −0.831877 0.62966734 CLSTN2 −0.8316578 −0.0616129 −0.3307678 0.49855509 GTPBP8 0.05263293 0.08803591 0.12022169 −0.8311549 42435 0.28832563 −0.477238 −0.8308778 0.19230068 HNRNPD 0.18338378 −0.6804024 −0.8305738 0.16050471 MBTPS2 0.0157453 −0.6124772 −0.8302701 0.38606525 RPL39 −0.0756471 0.15926055 0.01084592 −0.829471 SMG1 0.44622043 −0.369879 −0.8288789 0.47281465 PCBP1 0.01433314 −0.8284412 −0.7390134 −0.1771649 PRRC2A 0.31915189 −0.2012566 −0.5119764 0.82592776 TNS1 0.31101782 −0.4718121 −0.8250795 0.52408358 TIMM8B −0.2764193 0.31007369 0.18058668 −0.8246337 PLAGL2 0.14293625 −0.1158242 −0.8221324 0.37347501 TENM3 0.41047309 −0.091705 −0.4755345 0.82147404 MLLT1 0.20208066 −0.2058262 −0.0349525 0.82104198 LAT2 0.82097457 −0.1832742 0.07354103 −0.279438 SETD1B 0.40483959 −0.2945494 −0.8206969 0.48389261 KIAA1958 0.59930088 −0.1756622 −0.8198741 0.07151379 LSM1 −0.3020394 0.34480664 0.33368229 −0.8191136 ZNF592 0.00247617 −0.1202697 −0.4118149 0.8180076 ADAMTSL1 0.25156762 −0.0303982 −0.8178706 −0.4151771 ZNF92 −0.1575241 0.12210341 0.01481409 0.81672964 KIAA1522 0.16347146 −0.4251744 −0.445729 0.81644284 SYNE1 0.57991828 −0.181169 −0.2037623 0.81586155 HCFC1 0.35373061 −0.2882014 −0.5591182 0.8145383 NME1 −0.1639874 0.13818927 0.10511808 −0.8143385 HELZ2 0.63364926 0.81426182 −0.1169531 0.78278495 CISD3 −0.0228505 0.07775769 0.20708068 −0.813324 ZNF124 −0.031357 0.07475476 0.18144363 −0.8111291 FAM189B 0.39203737 −0.8097164 −0.7890085 0.39535966 TPT1 −0.1378906 −0.1575933 0.02870474 −0.8093746 RPS7 −0.103865 0.14510085 0.16029106 −0.8092512 COX5B −0.1190987 0.31259579 0.11797873 −0.8091611 RPS14 −0.1048589 0.20532268 0.09554905 −0.8077213 TANC2 0.39889691 −0.2159074 −0.6530988 0.80712455 TMEM14B 0.0661944 0.09143667 0.05982025 −0.8064157 FIS1 −0.1076721 0.17633828 0.00063911 −0.8060077 IGF1R 0.41095629 −0.2472216 −0.4883125 0.80494545 PSKH1 0.14922312 −0.8032981 −0.6000047 0.10837456 PPARGC1B 0.53861154 −0.8030216 −0.6181232 0.42281767 ZMAT3 0.39405547 −0.316103 −0.8028064 0.26457182 LRRC45 0.06369296 −0.0251713 0.39008585 0.80272564 AHNAK 0.80252471 −0.3304762 −0.7140354 0.64920927 DTX3L 0.41134465 0.80231874 −0.2993922 0.48085892 TGFBI −0.2570389 0.20078175 0.80007934 0.3704835 ATHL1 −0.4820053 0.05610773 0.37925368 0.79979154 RPS16 −0.0793584 −0.1040892 0.27233511 −0.799492 RPL35 −0.0450226 0.22842584 0.08062743 −0.7976596 SRP68 0.30247772 −0.7973084 −0.6918842 0.11623962 CENPE 0.23065233 −0.0413186 0.07030087 0.79692695 MRPL14 −0.0778284 0.19039514 0.11679956 −0.7968487 MDC1 0.18231103 −0.1840901 −0.7967524 0.39226963 TAGLN −0.1880335 0.23825082 −0.0002553 0.79664514 RRAGC 0.24873646 −0.2194246 −0.7960555 0.11665213 PRLR 0.26642442 −0.1394492 −0.2929194 0.79468347 LSM10 0.04944863 0.04640834 0.13394797 −0.7933342 SCOC −0.0486636 0.01196196 0.11514851 −0.7927906 CBLL1 −0.071392 0.11923917 −0.0644541 0.7925952 NID1 0.18092863 −0.1820773 −0.402495 0.79196821 CD9 −0.2391149 0.09497988 0.11751343 −0.789786 COX7A2 −0.1193055 0.35903906 0.14123531 −0.7895833 CD37 0.49670855 −0.1425112 −0.3714225 0.78933122 COPRS −0.1437362 0.28611786 0.07522103 −0.7885504 ASPM 0.33369108 −0.0784854 −0.1079878 0.78840583 WIZ 0.15082338 −0.0705928 −0.2584074 0.78780715 BST1 −0.209103 0.47712543 0.73517824 −0.7874461 PALLD 0.39694283 −0.1592997 −0.4549311 0.78671184 YLPM1 0.34176731 −0.4217563 −0.7859372 0.36717171 NOTCH1 0.45086414 −0.1304755 −0.2410426 0.78579311 CIC 0.25634133 −0.1177541 −0.1046079 0.78541621 ZYX 0.07922594 0.06511483 −0.3625228 0.78421339 TIMM10 −0.1540232 0.28267365 0.226671 −0.7840437 NIPSNAP3A 0.00469986 0.02211522 0.09744615 −0.7839678 FIGN 0.22682535 −0.0084107 −0.7837551 0.27918817 FAT4 0.78308508 −0.1484281 −0.6125628 0.69316549 ROBO1 0.14394207 0.00630321 −0.2918826 0.78262364 NR2F2 0.34044348 −0.2904713 −0.6770023 0.78192188 COMMD8 −0.1638725 0.08006183 0.07059501 −0.7818436 SERPINE1 −0.3523706 0.09793959 0.78112786 0.12019996 TMEM256 −0.0413693 −0.0573964 0.21214912 −0.7799032 UBR4 0.58840114 −0.3675312 −0.7789172 0.72565492 HECTD4 0.37131594 −0.3080995 −0.7786593 0.40814595 RPS6 −0.0963535 0.15548676 0.08034564 −0.7784045 CTDNEP1 0.29334372 −0.1067906 −0.7770331 0.2130949 LOXL2 −0.0336902 −0.3188399 −0.2365684 0.77685804 USP42 0.26802881 0.13249488 −0.2979633 0.77638395 PTPRJ 0.18580018 −0.2979844 −0.7740726 0.35677512 CABIN1 0.30310761 −0.0876353 −0.2532643 0.77387115 SOGA1 0.51105214 −0.2060559 −0.7736271 0.4511261 DST 0.7729289 −0.2501636 −0.5746267 0.70327288 GNG11 −0.0349802 0.01810362 0.45306584 −0.7726608 TRRAP 0.43809068 −0.4272642 −0.772268 0.45267478 UROS −0.0284145 0.11843949 0.00560396 −0.7716316 ERH −0.1117409 0.19354875 0.16762421 −0.7711759 RPL34 −0.0692139 0.1183294 0.24209863 −0.7711529 RAB40B 0.31661695 −0.1574102 0.13823004 −0.7705081 DDIT3 0.03874243 0.40775201 0.56825392 −0.7698485 NFIA 0.37702409 −0.1676769 −0.7688595 0.21744402 MGRN1 0.14211351 −0.2371295 −0.7688408 0.35480674 GPNMB −0.0055129 0.05361348 0.76861783 0.28883015 EPAS1 0.11013651 −0.0734968 −0.3277844 0.76809628 TRIP4 0.1565607 −0.7680757 −0.2943887 −0.1470014 FAM96B −0.0488291 0.19102142 0.11482978 −0.7676815 LSMD1 −0.0470343 0.26338638 0.0664862 −0.7661386 SERPINB6 −0.0286489 0.01085542 −0.0527733 −0.7657182 PODXL 0.04990762 −0.7656351 −0.4796134 0.38991377 KIAA0895L −0.3972427 0.0302244 0.76470905 0.22345461 HAS2 −0.5691384 −0.6286967 −0.7626376 −0.1724125 DGKH 0.08549837 −0.3301811 −0.762435 0.46993266 PTCH1 −0.4050242 −0.2322929 −0.5125555 0.76188367 FOXRED2 0.2911416 0.06242902 −0.4776138 0.76133341 CSF1 0.18249634 −0.0037474 0.03016121 0.76098925 FLYWCH2 −0.085166 0.07676486 0.06937554 −0.7605429 SAP130 0.2998304 0.1168796 −0.587572 0.75983942 ALKBH7 0.04656605 0.14162516 0.39077591 −0.7587919 NDUFA1 0.05723049 0.23994137 0.17208478 −0.7586538 TARDBP 0.18082544 −0.758394 −0.5073501 0.22415123 MYL6 −0.1088926 0.19294293 0.07178039 −0.7582488 PACS1 0.21995978 −0.17497 −0.7581394 0.57138478 GYS1 0.0617858 −0.0821535 −0.2399361 0.75732173 GSTO1 −0.1683602 0.07042909 0.06744613 −0.7560615 TNRC6B 0.47534861 −0.2716117 −0.5624099 0.75567458 POLB −0.0697952 −0.1862425 −0.0227756 −0.7556041 ARHGAP1 0.04601187 −0.1672981 −0.1700233 0.75515187 C10orf76 0.1826102 −0.7550102 −0.1842698 0.09295404 FUNDC2 −0.0673324 −0.1121169 0.00299169 −0.7549547 CHTF8 0.21582465 −0.7544197 −0.0754046 −0.0249082 SH3PXD2B 0.16600832 −0.2602101 −0.2589705 0.75413768 POLR2F −0.0499993 0.25042289 0.11836952 −0.7537528 MPC1 0.05449976 −0.0440483 0.2042987 −0.75338 SELT −0.0544388 −0.0187135 0.06242997 −0.7533545 PARP14 0.393569 0.75271806 −0.0106497 0.50233629 CHCHD2 −0.1179104 0.15237015 −0.0282455 −0.7526611 CBL 0.38774294 −0.1684004 −0.577353 0.75180148 CGNL1 0.53108476 0.75071271 −0.1217007 −0.3856639 WNK1 0.34198436 −0.3607998 −0.7485527 0.72044065 SNRPD2 −0.0133937 0.23330077 0.13849688 −0.7484995 DLGAP4 0.13459903 −0.3127174 −0.7482435 0.52364621 PDCD10 −0.0898093 0.06343052 0.26653888 −0.7480098 MBNL3 0.16061597 −0.3917519 −0.500039 0.74671738 POGZ 0.00988818 −0.0448218 −0.5682575 0.7459217 PFDN5 −0.1625893 0.13888799 0.19166138 −0.7453253 NUP214 0.15601117 −0.0046293 −0.6036456 0.74416114 TBCA 0.055192 0.18619778 0.25897634 −0.7440489 EIF5B 0.1730178 0.04756018 −0.3010001 0.7439431 RNF26 0.18626802 −0.5766802 −0.7436638 0.35169347 DAG1 0.20057417 −0.0143688 −0.2456884 0.7431593 C18orf54 0.38093522 −0.5884877 −0.7412145 −0.3347837 DOT1L 0.16584165 −0.1330813 −0.2489036 0.74043237 WIPF1 −0.011798 −0.2568072 −0.7399232 0.56279199 RPS29 −0.1852548 0.1804712 0.15456511 −0.7378582 PGRMC2 0.06212032 −0.426523 −0.7372997 0.08295774 TET2 0.15915101 −0.2542669 −0.2007536 0.73690033 CCNYL1 0.25136473 −0.7368267 −0.7003753 −0.0593294 EIF1 0.00609732 −0.7360113 −0.4955177 −0.0752403 MYO18A 0.73567853 0.12921304 0.03202898 0.42485317 MAML2 0.226234 −0.0442136 −0.7353574 0.58903297 PIP5K1C 0.29006792 −0.1600166 −0.4797228 0.73498584 AHDC1 0.5993769 −0.7338343 −0.5498448 0.61378138 TFCP2 0.02149895 −0.732314 −0.1907679 −0.0433242 PDE6D −0.2191787 0.18466146 −0.0721636 −0.7319449 DNPH1 −0.0009827 0.43033483 0.05018163 −0.731735 MRPL11 −0.2065935 0.20420573 0.0968399 −0.7316706 PSME4 0.10201225 −0.3653041 −0.7315674 0.38802209 RPL36 −0.084052 0.34458076 0.08880894 −0.7315631 SERTAD2 0.24002861 −0.1227343 −0.730537 0.67647607 RPL41 −0.2716021 0.13563552 0.52903602 −0.729796 COL7A1 0.11995451 −0.0878979 0.72949751 0.65470857 AKNA 0.28230134 −0.1777801 −0.7283938 0.65683736 SCD −0.2419056 −0.1619073 −0.1931494 0.72703107 CKS2 −0.1410467 0.14312957 0.28343282 −0.7267607 ATXN2L 0.01859455 −0.1503499 −0.7265556 0.44844491 HTT 0.49508707 −0.5529385 −0.7259824 0.53105367 ERC1 0.37104825 −0.3724619 −0.7258559 0.21760705 NF1 0.42180479 −0.2394217 −0.725719 0.513972 MED12 0.27650641 −0.2342678 −0.3113031 0.72569994 TLE4 0.12144083 0.12978182 −0.0361115 0.72560109 LPP 0.50431793 −0.2446502 −0.7254972 0.49327753 SLC9A8 0.03875178 −0.2144372 0.00618336 0.72538523 EGFR 0.38312923 −0.2998069 −0.3962258 −0.7249009 DPY30 0.0656528 0.21761208 0.16088905 −0.7242833 EPHX4 −0.1245721 0.44176576 0.03589257 −0.7240398 PRPF8 0.37693059 −0.4239123 −0.7235068 0.4921559 ZNF618 0.41176559 −0.7229669 −0.6866991 0.38673342 BCL6 0.22823065 0.04170323 −0.2332596 0.72287798 CRLS1 −0.1251186 0.1250749 0.1587039 −0.7226358 FAM193A 0.04144894 −0.2711487 −0.2929548 0.72248874 NDUFAB1 −0.0775336 0.10604635 0.20104417 −0.7220407 CNOT4 0.05292941 0.12393884 −0.4111783 0.72189865 INPP5D −0.7216967 −0.6089731 −0.0359974 0.50315767 SAMD9 0.34438331 0.43587608 0.23156093 0.72114206 FMNL1 −0.0834219 −0.7211033 0.15431922 0.60694859 ID3 −0.0144504 0.27775256 0.17374693 −0.7202375 SEMA6A 0.01900555 0.20727855 −0.7193101 −0.2190822 KIAA1671 0.36509288 0.0321638 −0.5091207 0.718559 BMPR2 0.25979634 −0.3695584 −0.7181442 0.45786169 WWTR1 0.09179175 −0.4702416 −0.7171373 0.10892678 SMARCD1 −0.0197837 −0.0282116 −0.1519902 0.71673871 HIST2H2AC −0.2313772 0.13777708 0.13924985 −0.7160745 PITPNB 0.11279214 −0.7155989 −0.5015428 0.01916005 STRA13 0.04236656 0.3744062 0.1215577 −0.7151861 RAVER1 0.21478404 0.1352911 −0.6702627 0.71509435 MZT2B −0.0149868 0.22641403 0.00839144 −0.7146902 NBEA 0.71446513 −0.1443396 −0.6738816 −0.6327659 RPS21 −0.0777348 0.12780467 0.25215885 −0.714458 GBF1 0.19767302 −0.1077357 −0.3115526 0.71368254 MACF1 0.71273782 −0.2650445 −0.6033934 0.62222288 TGFB1 0.04520907 −0.4679573 −0.4839856 0.71241656 UBA7 −0.6277551 0.10560167 −0.7120835 0.5755638 PURB 0.3164115 −0.4147733 −0.7119658 0.29828456 AXL 0.17297792 0.00271035 0.54846146 0.71101284 PER2 0.71004508 0.3531763 −0.1795497 0.5916787 KIFC2 0.08580007 −0.0209064 0.70865803 0.43097591 ARHGAP17 0.15876769 −0.307002 −0.7081354 0.30144804 MRPL41 −0.096754 0.35368377 −0.0431797 −0.7080853 ATG2A −0.0158203 −0.0843652 0.01655914 0.70785673 CLEC16A 0.12376776 0.0158437 −0.4114063 0.707486 LSM6 0.00839272 0.24468743 0.11536032 −0.7073889 GUK1 −0.045038 0.11951347 0.01707708 −0.7071225 HRSP12 0.34779115 0.23142426 0.38655933 −0.7069435 MKL1 0.12364429 −0.0876691 −0.1813776 0.70680803 HIGD1A −0.1541454 0.06703937 0.13931492 −0.7068047 BAZ2A 0.27087643 −0.2024223 −0.4109497 0.70613196 ZXDC 0.07622292 −0.2076556 0.03666342 0.70611099 OSBP 0.15427342 −0.4345115 −0.7060369 0.29556177 ZNF689 −0.1220564 0.25835345 0.15268599 0.70597013 KLF6 0.27019634 −0.7058116 −0.6207123 0.05114733 PHF10 0.05655259 −0.3345838 −0.7055559 −0.0003914 GLRX2 −0.0154692 0.25891862 0.35878476 −0.7053188 CCDC174 0.11668438 0.14181537 0.02682206 0.70500187 BLVRB 0.1336541 0.31060346 0.10027175 −0.7044515 PTPN23 0.01972183 −0.4015182 −0.7041025 0.43721098 EMG1 −0.2200704 0.18357813 0.07894595 −0.7038584 MYL12B −0.1642617 0.16047911 0.06633748 −0.7033651 ZNF524 −0.0261445 0.07582754 −0.0248164 −0.702734 ATP6V0B −0.2075754 0.21741715 0.06651797 −0.7020792 MYEOV2 −0.1171961 0.05216563 0.1165658 −0.701866 CDKN2AIPNL −0.0156442 0.00657345 0.0848714 −0.7016626 ARL16 −0.3524384 0.0614444 0.00331368 −0.7012973 MAFB 0.52197647 0.70068724 −0.4615867 0.31545919 MTF1 0.28471497 −0.5257905 −0.5880104 0.70009838 MYO1F 0.54607575 0.01897796 0.69937628 0.30594668 ZCCHC24 0.42829079 −0.1630082 −0.3868945 0.69927792 RP11- 0.34466969 −0.6876957 −0.4673936 0.69896676 1055B8.7 C20orf24 −0.0464426 0.36200074 −0.070348 −0.6983517 HIST1H4B −0.3025428 0.12150336 0.04573338 −0.6965536 RRBP1 0.14382158 0.06177326 0.01469708 0.69632725 SF3B4 −0.0122454 −0.2830901 −0.5210705 0.69507176 RBM47 0.69470234 0.31734915 −0.1631805 0.38064037 NFYA 0.08597344 −0.6945983 −0.358348 0.09846193 PTPRS 0.25738687 −0.0894199 −0.2596879 0.69454441 EPS15L1 0.2011242 −0.694443 −0.43677 0.49688921 PEX2 −0.0654033 −0.0165174 0.05594961 −0.6943061 IFITM3 −0.1671234 0.48203094 −0.0679501 0.69341979 PHPT1 −0.0849785 0.22920037 0.12021693 −0.6931218 ZFAT 0.12955857 −0.105526 −0.1542274 0.6929942 MLXIP 0.29574583 −0.4859208 −0.6927137 0.45213406 SNRPB −0.0522575 0.16015699 0.11578603 −0.692679 SEC16A 0.33121856 −0.356288 −0.5086548 0.69236329 NEK9 0.2099789 −0.691938 −0.1993717 −0.2291059 CAMK1 −0.2879642 −0.1073967 0.1886332 −0.6918794 HUWE1 0.64680448 −0.2516549 −0.6610089 0.69130864 UQCC2 −0.0780903 0.28438104 −0.0039675 −0.6912245 ZNF703 0.02118213 −0.4464337 −0.690966 0.59041746 TMEM251 0.2529558 −0.4407704 −0.1814064 −0.6902947 BOD1L1 0.30661434 −0.1677215 −0.2478845 0.68990842 RPL31 −0.1042739 0.18195522 0.24169139 −0.689805 RPS8 −0.0722204 0.23475319 0.09595389 −0.6895767 FAM214B 0.22963929 0.1963179 0.6893649 0.46258683 TMSB4X −0.0491079 0.12849384 0.16832894 −0.6885786 RNF7 −0.1143546 0.14505612 0.25273506 −0.6883554 MAP1LC3B 0.01897982 −0.6317002 −0.6881106 0.03555737 BICD1 0.20758907 −0.6880817 −0.6697518 0.27824299 TLK1 0.03497865 −0.1769765 −0.6880664 0.3242051 RPL24 −0.0182891 0.21094074 0.07940853 −0.6876611 MGLL −0.2369213 −0.0206939 −0.6875989 0.31725033 PDRG1 −0.1229914 0.06867962 0.32776139 −0.6870351 SLX4 0.40052456 −0.1435945 −0.3020903 0.68636662 TMA7 −0.061059 0.06993837 0.21389414 −0.6857448 TMEM126B −0.1269055 0.09187004 0.40594915 −0.6856293 FOXO1 −0.6846492 0.17118209 −0.4213793 0.58409549 MAP3K7CL −0.438062 −0.4262716 −0.301055 −0.6833629 POLR2G −0.1469537 0.24141416 −0.0308052 −0.683307 CLASRP −0.2218105 −0.1034132 0.37471402 0.68321257 LRRC8C −0.6827572 −0.1862476 −0.4784822 0.32815071 MRPL1 −0.1527666 −0.024246 0.23547482 −0.6827347 SYVN1 −0.0001284 0.25249928 −0.1135056 0.68217215 SIRPA 0.03009069 −0.2327874 −0.0732276 0.68155812 CASP2 0.1249507 0.03734615 −0.2469114 0.68132013 CDK4 −0.1193635 0.20776206 0.04619515 −0.6807022 RECK −0.0057595 −0.0407534 −0.1237097 0.68049107 NDUFS4 −0.0355866 0.21776783 0.23579147 −0.6801904 ZNF460 0.44379629 −0.2456255 −0.5045584 0.67939411 FXYD5 −0.1721804 0.25340178 0.13590228 0.67927502 ANKRD52 0.33265339 −0.2005057 −0.6788763 0.67651402 RPL35A −0.0805732 0.19241707 0.21813899 −0.6788188 BUD31 −0.1413041 0.20222861 0.27506481 −0.6785299 SGK223 0.07891851 −0.0638443 −0.0779862 0.67818531 UQCRQ −0.1208104 0.29858669 0.13249748 −0.6780903 NR2C2 0.35099856 −0.1815148 −0.3598921 0.6779802 WDTC1 0.0369491 −0.0054894 −0.0613792 0.67762392 RPS19 −0.0657441 0.264047 0.03617435 −0.6769226 DYNC1H1 0.67666299 −0.3286523 −0.5360687 0.66019466 ISCA2 −0.0930466 0.36064507 0.06845716 −0.6766068 EFCAB13 −0.4879249 −0.5514199 −0.5085469 −0.6763095 LPAR6 0.00809963 0.04013862 −0.6762345 −0.3505345 SNRPA −0.1132638 0.2610254 −0.0197595 0.67610147 RPS9 −0.0622337 0.19768013 0.02876004 −0.6735017 PATL1 −0.1398499 −0.0147962 −0.273253 0.67326926 ARID1B 0.27640285 −0.2431486 −0.6725589 0.19750408 PRDM2 0.12754439 −0.4792706 −0.6721999 0.2550488 KMT2E 0.14138375 0.03302055 −0.6721465 0.38582263 DPM3 −0.3141782 0.22541281 0.14423821 −0.6718572 NBEAL2 −0.0259705 0.0875084 0.01440937 0.67159457 HK2 0.20256083 −0.6713647 −0.3900092 0.41017983 ATP6V1G1 −0.1014226 0.19680945 0.19800597 −0.6712824 ZMYND8 0.14616929 0.03795236 −0.1947255 0.67105713 ZNHIT1 −0.1638636 0.24330263 −0.0038293 −0.6708862 RNF111 0.25614978 −0.1891329 −0.6700811 0.39697402 ELMSAN1 0.2480769 −0.0454292 −0.6698957 0.59761705 NDUFA2 −0.1894207 0.04456546 0.13522255 −0.6689256 AP2B1 0.22070255 −0.5345326 −0.6680332 0.21354084 NPRL3 0.08138371 −0.3975667 −0.667216 0.44778492 NDUFB7 −0.0584689 0.50413794 0.09651173 −0.6667978 VDAC3 −0.1016561 0.16172422 0.082809 −0.6664728 COX4I1 −0.1179971 0.19833835 0.10473529 −0.665061 LENG8 −0.2480121 −0.290675 0.02397865 0.66447969 POM121 −0.0373585 −0.3781447 −0.6644068 0.61685883 TPRG1L 0.23797832 −0.6643566 −0.2855898 0.08067928 ZFYVE1 0.25813763 −0.2455746 −0.0488257 0.66425522 DDX58 0.22708479 0.66409033 −0.2960837 0.53917234 ANAPC11 −0.0310072 −0.0675648 0.16452069 −0.6635919 FAM195A −0.1280468 0.5476451 0.02063211 −0.6634027 FBL 0.20545222 −0.6632771 −0.0995856 −0.2496504 COL4A1 0.06097682 0.08222265 0.05065298 0.66257605 SAP18 −0.0592676 0.25766103 0.13588158 −0.6621962 COL8A1 0.34542176 −0.0039299 −0.661274 −0.0296311 GPX1 −0.2114787 0.3234247 −0.1068436 −0.6612646 C1QBP −0.1691133 0.20664222 0.09452385 −0.6612329 TRIM25 0.13370604 0.01988975 −0.0570708 0.6610546 BOLA3 0.03820847 0.15090116 0.1162993 −0.6604122 AKAP13 0.46754593 −0.1767451 −0.3475739 0.66014789 MTERF −0.1274601 −0.1146205 0.12889352 −0.6594901 TTC28 0.23124418 −0.0905523 −0.6594336 0.5301488 VBP1 −0.0939302 0.04120119 0.19609118 −0.6591449 PLEKHM1 0.10557984 −0.346892 −0.3085159 0.65913011 MAP1A 0.65870448 −0.1268322 −0.4585143 −0.0564045 RFX2 0.16660717 0.30261854 −0.0918528 0.65826559 SPTBN2 0.65773897 0.07256079 0.06462278 −0.3736431 SLC9A1 0.21555496 −0.1181106 −0.3775045 0.65755719 RNASEH2C −0.129623 0.20559294 0.08920342 −0.6569488 RNASEH2B −0.1555055 0.0057283 0.11718796 −0.656557 ZNF507 0.23508962 −0.430751 −0.6555491 0.25529056 ANKRD11 0.25388253 −0.4235929 −0.3709929 0.6543245 ZC3H7A 0.22862688 −0.2936765 −0.6540382 0.30215403 CD63 −0.0493749 0.12690151 0.12110333 −0.6539269 FASN 0.32764364 −0.5301338 −0.3561973 0.65373234 VRK1 −0.100069 −0.1563579 0.17672029 −0.651943 SIPA1L3 0.25763115 −0.3247721 −0.3480234 0.65173291 TRAPPC2L −0.1142541 0.13288888 0.2544896 −0.6513163 LSM2 −0.1948055 0.00335126 0.18112901 −0.6512747 RPA3-AS1 0.12706361 0.02499609 0.12440744 −0.6504324 SGSH 0.18211862 −0.6499683 −0.3447606 0.59514005 CNTNAP1 0.62568463 −0.3610579 0.18420182 −0.6498898 ASXL2 0.45107431 −0.3562411 −0.6497617 0.61528649 ZC3HAV1 0.36946724 −0.0151081 −0.3182312 0.64967706 HNRNPUL2 0.330445 −0.649644 −0.2923807 0.57883747 UQCRH 0.02889511 0.1274419 0.09708469 −0.6496262 COA5 −0.1481261 0.31191961 0.18182268 −0.6493659 FOXP4 0.27457607 0.08373616 −0.6492951 0.59499349 CLSTN1 0.09314359 −0.2178548 −0.416466 0.6492879 HIST1H2AC −0.221942 0.10300129 −0.0643994 −0.6488332 RABEPK −0.2423888 0.37029466 0.20758468 −0.6487692 GPATCH8 0.36065644 −0.1654673 −0.4190748 0.64843932 ATP11A 0.20232777 −0.3616228 −0.3798197 0.64659016 DROSHA 0.146996 −0.2206603 −0.6461854 0.42486847 SAFB2 0.12624596 0.00681115 0.03749066 0.645737 SOS1 0.16531618 −0.2765128 −0.4532642 0.64557477 SMC1A 0.23168708 0.000014 −0.0382686 0.64520153 SLC37A2 −0.4601264 −0.3077019 0.64472407 0.46548704 UNC50 −0.0430429 0.2375202 0.24490606 −0.6445635 ACTR10 0.01336683 0.04280885 0.11937769 −0.6444256 IDS 0.17345858 −0.1524527 −0.6055529 0.64438574 IDS 0.17345858 −0.1524527 −0.6055529 0.64438574 TMSB10 0.00428988 0.25987954 0.03947516 −0.6441701 BAG3 0.01798977 0.02901065 −0.1994011 0.6433041 SERF2 −0.088517 0.14343808 0.02776844 −0.6428479 POLR2L 0.05690065 0.33861544 0.00508111 −0.6426752 LGALS3 −0.2498782 0.00758887 0.05489277 −0.6424445 ENG 0.23001436 −0.5838006 0.07091641 0.64236037 ZFAND1 −0.1112874 −0.0511364 0.25878969 −0.6423553 TIAL1 −0.1217041 −0.6423042 −0.5904268 0.00568302 RPL38 −0.0669938 0.2804294 0.17695113 −0.6421883 HSPG2 0.53877794 −0.3956217 −0.4659358 0.64198319 SF3A1 0.08170197 −0.2643141 −0.4414966 0.64192559 DMXL2 0.37273976 −0.2201187 −0.1950206 0.64184882 ZCCHC14 0.48564047 −0.2233681 −0.6417158 0.58466688 COMMD10 −0.0465881 −0.0667263 0.19938607 −0.641105 THBS1 −0.0500019 −0.2527757 0.64074912 0.21497247 SOX11 0.30768901 −0.3239856 −0.2209573 −0.6407452 PHF12 0.26237749 −0.0678985 −0.2444427 0.6403214 HERC1 0.63991795 −0.1599073 −0.1973418 0.48571048 THOC2 0.11956975 0.0040928 −0.0469516 0.63976694 UBN2 0.28652923 −0.3650121 −0.6394169 0.36378419 MSI2 0.6392879 −0.1500156 −0.0290522 0.30120435 LARP1 0.21666992 −0.4125232 −0.4583164 0.63921391 RWDD1 −0.1211373 0.10119799 0.11530031 −0.639069 RBM25 0.07266134 −0.0357925 0.13858936 0.63895869 BPTF 0.30462507 −0.2992659 −0.6385147 0.43841705 TOB2 0.13533031 0.04276188 −0.286996 0.63808771 RPS5 −0.0962698 0.2682929 −0.009331 −0.6378146 PHF15 0.63725539 −0.2936113 0.08938201 0.30821255 PPIL2 0.08179893 0.02592571 −0.0591188 0.63706339 EXOSC2 −0.0891163 0.04418046 0.03380647 −0.6368929 MRPL22 −0.111474 0.04377597 0.09855778 −0.6361087 KIF13B 0.63609306 −0.4912713 0.04309151 0.30249692 BACE1 0.08248482 −0.0932679 −0.6360369 0.36763469 RREB1 0.36929873 −0.2721441 −0.6356217 0.59453005 USP13 0.10721109 −0.1650747 −0.6354058 0.18024643 ASH2L 0.0284543 −0.6352788 −0.1526158 −0.0244145 SZT2 0.20336875 −0.1464573 0.08648636 0.63501242 PER1 0.17396108 0.16514707 −0.3825164 0.63496443 ODC1 −0.0802411 0.07120686 0.11517868 −0.6343775 FAM96A −0.0696096 0.059885 0.22833084 −0.6341768 FDX1 −0.1965326 −0.0798717 0.01876547 −0.6334012 SAMD4B 0.12636222 −0.029846 −0.3521489 0.63249431 S100A4 −0.3110807 0.20360646 −0.0618069 −0.6316783 RUNX1 0.2277922 −0.2247395 −0.6309345 0.49990091 CHD6 0.3341391 0.0443692 −0.144227 0.62964069 GIGYF1 −0.0621294 −0.2072601 0.28963001 0.62956052 SLC29A1 −0.1630535 −0.0247497 −0.088028 0.62940686 FBN1 0.45360776 −0.0980688 −0.0543201 0.62938044 GRINA −0.1498919 0.16185766 −0.2666019 0.62936135 AP1S1 −0.0780121 0.24562243 0.11483684 −0.6290629 NDUFB5 −0.0104284 0.09214701 0.30355745 −0.6288479 COL6A3 0.10017429 −0.208172 −0.6286416 0.56806965 KIAA1549 0.49430312 −0.2430173 −0.6280905 0.0273081 TET1 0.14602761 −0.1757865 −0.6279997 −0.2903597 HELZ 0.55744685 −0.1048788 −0.6278457 0.49445915 ADAR 0.22871069 0.11872656 −0.2449334 0.62776731 HNRNPA3 0.05047238 −0.2185763 −0.6277281 0.33617163 LYRM4 −0.1453657 0.37440031 0.00068331 −0.6272341 KLHL17 −0.1640517 −0.3485359 0.62678406 0.34482479 ZC3H13 0.22032524 0.06571592 −0.2938271 0.62665868 ATXN2 −0.030169 −0.3537733 −0.6266146 0.38922886 PRDM1 0.27835792 −0.0365875 −0.2959493 0.6264806 IPO8 0.27967744 −0.5675011 −0.6263311 0.04071775 THOC7 −0.1401775 0.04886786 −0.0402314 −0.6262613 ABCA2 0.1830956 −0.3900777 −0.0468332 0.62577825 TSC22D2 0.34222883 −0.1724656 −0.5858485 0.62544389 NSMCE2 0.05260604 −0.0605055 0.12558923 −0.6252565 ANLN 0.16392602 0.00018935 0.04656657 0.62480768 UFM1 −0.1435817 −0.096424 0.21603745 −0.6241482 BCL9 0.56159461 −0.0470708 −0.6241088 0.37093781 TMEM131 0.08083164 −0.3000232 −0.6240924 0.52870683 SSH2 0.24652964 −0.3771303 −0.6238067 0.55714596 RAB5B 0.09809168 0.10805603 −0.429187 0.62375699 TNRC18 0.48784284 −0.5145162 −0.360038 0.62357041 ATRAID −0.0562984 0.04785495 0.00724475 −0.6230705 MANBAL 0.10492491 −0.6230144 −0.0353837 −0.5916132 HIF1AN 0.26065744 −0.5477942 −0.6228683 0.1757314 MIER2 −0.032639 0.10288943 −0.0257409 0.62276739 KIAA2018 0.44732845 −0.2438708 −0.6225954 0.58429501 KIAA1644 0.6224263 −0.5491356 −0.0680371 0.30529746 MDN1 0.56147949 −0.3797687 −0.4797704 0.62183271 ACBD6 −0.2437065 0.24631733 0.11890892 −0.6213328 TAF11 −0.1159853 0.05337567 0.02537324 −0.6213313 BCL7C 0.0559302 0.22597951 −0.0512092 −0.6197418 PRDX4 −0.1026349 0.03493906 0.04270317 −0.619098 SH3PXD2A −0.541106 −0.3694972 −0.373055 0.61827145 NDUFA4 −0.0603049 0.1236355 0.19939653 −0.6182119 COX7A2L −0.1056601 0.19660076 0.12680079 −0.617988 COL1A1 0.18281814 −0.617397 −0.4845399 0.28285743 PLGRKT −0.311108 0.11616741 0.01102185 −0.6173045 PHLPP1 0.30927483 −0.2443999 −0.1989871 0.61716064 RPL7 −0.2782613 0.61682342 0.32098952 −0.2178949 NDUFB11 −0.067291 0.10653609 0.00501105 −0.6162535 TOMM22 −0.0401889 0.21298331 0.08402675 −0.616179 KIAA0195 0.07427801 0.06880772 −0.0686125 0.61599126 FBN2 0.55820473 −0.1420739 −0.3621148 0.61595954 VAPB 0.28774822 −0.3554221 −0.6152536 −0.1481935 CSNK1D 0.41494697 −0.6152464 −0.0509978 0.44910483 TAF15 0.33759619 −0.3356234 −0.615073 0.37148656 RPS3 −0.0802883 0.10389728 0.23470506 −0.6148063 WDFY3 0.56172422 −0.1519171 −0.421653 0.61439379 CHMP5 −0.1253241 0.14793429 0.18705985 −0.6142318 TIMM17A −0.1276591 0.18164992 0.1907365 −0.614216 KREMEN1 0.1334742 −0.4707499 −0.3061423 0.61393689 CAPZB 0.14808062 −0.6138492 −0.2438958 0.10140313 MRPL52 −0.1489676 0.1944622 0.16738686 −0.6124055 SEZ6L2 0.04907384 −0.0422598 −0.3426457 0.61207377 NPEPPS 0.11861628 −0.3073185 −0.6118175 0.25492211 ZBTB4 0.23113678 −0.0570435 0.19002955 0.61172573 EMC4 −0.1228382 0.22689068 0.13260175 −0.611678 SUPT6H 0.23794797 −0.1421081 −0.2582735 0.61118681 ZC3H4 0.16508414 −0.213659 −0.0953573 0.61101321 ATP5L −0.0788192 0.21774803 0.13371676 −0.6105035 C14orf119 −0.2407412 0.15430162 0.2172443 −0.6098228 PHIP 0.39174453 −0.1444776 −0.3386133 0.6098121 CNOT1 0.2701859 −0.3676084 −0.6097591 0.4193538 PAK2 0.10707895 −0.1414927 −0.6093931 0.47588181 CORO2B −0.2820641 −0.5596266 0.18289952 0.60923332 DHRS3 −0.063908 0.16501223 −0.6090997 −0.335804 CAD 0.25501667 −0.2856717 −0.2589896 0.60869814 MED14 0.11252078 0.08768649 −0.4584954 0.60834197 ITPR1 0.23215426 −0.2131143 −0.1774731 0.60807991 EAPP 0.07055882 0.03035581 0.03935178 −0.6080488 PLEC 0.60803851 −0.4390697 −0.0739505 0.51655082 IRS2 0.40684587 −0.0133624 −0.3694001 0.60775216 EME2 −0.0603293 −0.0819053 0.60761526 0.57194236 RPL13 −0.1221995 0.22944023 0.10649636 −0.6070348 CISD2 0.0203557 0.0234977 0.01659216 −0.6069196 CIRH1A 0.00677022 −0.6067432 −0.3364061 −0.0358311 ASNA1 −0.0318356 0.15325642 0.13451551 −0.6066209 COMMD2 −0.0810984 −0.0606433 0.223466 −0.6065546 ECM1 −0.1654676 −0.1230485 0.54896424 0.60632336 HNRNPH3 0.01309698 −0.1492037 −0.0225629 0.60622609 PNISR −0.2427846 0.02565595 0.389415 0.60572638 ERV3-1 −0.0732115 0.12219481 0.24200652 0.60567946 MYL6B 0.09074426 0.09537939 0.02748779 −0.6055049 RNF24 0.28610542 −0.4172479 −0.4189513 0.60501631 ARF5 −0.1432807 0.05165503 0.12897223 −0.6045449 TMEM255A −0.1903353 0.29143604 −0.0083233 0.60427502 EML4 0.18751478 −0.1238423 −0.1185083 0.60411615 BDP1 0.19032831 −0.1879546 −0.0369604 0.60390581 NUDT22 −0.1024498 0.20503822 −0.0921023 −0.6038555 AHSA2 −0.6037547 0.04159724 0.48348561 0.28401614 ZNF264 0.32088889 −0.0101949 −0.0735916 0.6035366 CPEB2 0.08370522 −0.2392846 −0.6034892 0.54243457 TTC23 0.04798991 0.17085039 0.22409696 0.60342208 TACO1 −0.0895552 0.37167266 0.15134275 −0.6033289 MAP1S −0.0259994 −0.2147379 −0.2504758 0.60328444 DNMT3A 0.20588714 −0.1486271 −0.0322866 0.60328435 FOXK1 0.33591078 −0.2783668 −0.2289421 0.6032517 TNIK 0.03369989 −0.2122443 −0.1543764 0.6032397 SIK3 −0.1062978 −0.0653288 −0.286771 0.6028454 NT5C −0.2495352 0.10965321 0.27200441 −0.6025438 CHIC2 −0.0915761 0.08842754 0.02863301 −0.6025347 TCEB2 −0.0783649 0.27046909 0.0879852 −0.602011 SERPINI1 −0.2388108 0.60182979 −0.1640421 −0.487902 SRGAP2 0.30025924 −0.2221885 −0.4238051 0.60140293 C19orf60 0.01221806 0.30748602 −0.1255583 −0.6012153 CEP170B 0.23372876 −0.0547418 0.05162296 0.60100307 MAP4 0.17126421 −0.1500567 −0.4624705 0.60095398 MAD2L2 −0.0952123 0.18975257 −0.1213884 −0.6006432 RAB14 0.17800202 −0.4698866 −0.6006394 0.21569399 USP4 0.17387147 −0.6005815 −0.3062356 0.08135675 ZFAND6 −0.0120998 0.0618661 0.07609014 −0.6000193 PTGS2 −0.5999766 −0.0931668 0.22761614 0.42806155 DVL3 0.08436021 −0.0199839 −0.154905 0.59987875 E2F7 0.00964041 −0.3086901 −0.4185547 0.59986224 WWP1 0.08456919 −0.3622396 −0.5998278 0.06716568 DIP2B 0.35171953 −0.1880126 −0.2502995 0.5996772 LCOR 0.37842293 −0.2895198 −0.5993783 0.39642696 SEPW1 −0.1901097 0.17462622 0.07091534 −0.5991882 KIAA0430 0.27070115 −0.2732841 −0.4988436 0.59775008 TAPBP 0.0185036 −0.0257369 −0.2317106 0.5974676 UBE2E1 −0.0565594 0.00661879 0.10511862 −0.597427 FAM120A 0.1037268 −0.1256171 −0.3178688 0.59705973 TMEM70 −0.0504234 0.07724659 0.06232425 −0.59679 PSMG1 −0.0780157 0.0824987 0.09446719 −0.5960468 PHF2 0.0881643 0.0027877 −0.0814045 0.59601232 PSMA5 −0.1296535 0.20694361 0.1437429 −0.595803 XAB2 0.1574293 −0.5956765 −0.332247 0.48675126 GLRX5 −0.2668158 0.11946854 0.08425422 −0.5956251 PPP3CB 0.06921434 −0.1173311 −0.595449 0.04938018 RBX1 −0.0213316 0.16994897 0.07484423 −0.5948079 AKT1S1 0.15038872 0.02430038 0.06395074 0.59440977 MYO9B 0.25433861 −0.149191 −0.1010071 0.59415302 PPRC1 0.03218728 −0.091823 −0.2092112 0.59406004 ATIC −0.1389259 −0.5939784 −0.3106664 0.49888503 GLCCI1 0.44525596 −0.062164 −0.5938561 0.3116879 KIAA0556 0.06188358 −0.1566237 −0.1413294 0.5937682 SMARCA4 0.20541582 −0.1028729 −0.2404313 0.59320434 CCNI 0.04095984 −0.2018985 −0.5931168 0.34594281 RAPGEF2 0.23467528 −0.2363952 −0.063387 0.59307649 CRTC2 0.00801942 −0.1122516 −0.1973212 0.59297285 MIDN 0.42175967 −0.5926738 −0.3772564 0.42222665 PRRC2B 0.36038622 −0.3142708 −0.2724403 0.59253672 REV3L 0.24725612 −0.0979766 −0.3359959 0.59181582 KANSL2 −0.2920008 0.25039404 0.03807063 −0.5914465 TMEM104 0.18818904 0.12319526 −0.0770083 0.59114827 PXN 0.08665454 −0.0901224 −0.0652852 0.59094062 MRPS15 −0.1130872 0.1760317 0.0356072 −0.5909397 NUS1 0.08006048 −0.5907841 −0.5344542 −0.0102702 ALG5 0.00016011 0.08647722 0.05725181 −0.5907632 MEF2D 0.11596095 −0.0058267 −0.4906656 0.59071354 NOTCH2 0.40154242 −0.1038908 −0.3358454 0.59040599 MAST4 0.00135045 −0.4313955 −0.2903037 0.59035163 GNA12 0.06164555 −0.5901113 −0.2360209 0.2583498 C11orf31 −0.0204896 0.42842653 0.08848079 −0.590111 ITGA7 0.52210286 −0.4203143 0.23098028 0.58991014 MRPL15 −0.2647672 0.12103246 0.08049235 −0.5897928 C6orf48 −0.1475908 0.20841532 0.27033495 −0.5897076 IL1B −0.5886053 0.11251734 −0.0360038 0.2320674 UBE2K 0.06171712 −0.5884734 −0.5252505 0.21226608 NDUFA11 0.01812048 0.12635441 −0.0273753 −0.5884594 ZSWIM8 0.10425038 −0.0013799 0.04770621 0.58818643 MYL12A −0.1560408 0.15997282 0.1133287 −0.5881379 ARHGAP35 0.28229929 −0.2836288 −0.2187161 0.5880784 TSC2 0.19872905 0.04537674 0.0250935 0.58768937 TMEM14A 0.31666037 0.08435895 0.18697062 −0.5873504 RPL28 0.20016387 −0.5581746 −0.1748918 0.58726685 SEC11C −0.0940956 0.21802591 0.03942679 −0.587025 DAGLA 0.44643849 0.13760796 −0.2180027 0.58681975 EIF1AX −0.0832341 −0.1496927 −0.0268283 −0.5867702 TGM2 −0.5866502 −0.4783712 −0.2921457 0.58223914 CLCN5 0.05479201 −0.167218 −0.293093 0.58637326 TRNAU1AP −0.0505374 −0.0212581 0.30168615 −0.5861854 SPTAN1 0.51018049 −0.1569346 −0.4037615 0.58608773 ABL1 0.24238688 −0.1384672 −0.1989861 0.58570561 RBAK 0.11892143 0.03128251 −0.0493609 0.58569666 ENAH 0.18670088 0.02747295 −0.0428755 0.58567301 PHLDB1 0.3306915 −0.1218639 0.09210687 0.58562536 WDR81 0.18992452 −0.1538014 −0.0062218 0.58527922 MIEN1 −0.0884499 0.02081678 0.04860133 −0.5851208 BAG1 −0.1090229 −0.0848868 0.03340944 −0.5851056 SCO1 −0.0593555 0.02941735 0.16855935 −0.5839784 NXF1 −0.1328586 −0.05777 0.25316062 0.58352688 C7orf50 0.04299535 0.23898008 0.02444089 −0.5833087 RPL32 −0.0934306 0.18937789 0.06983722 −0.5826075 BCOR 0.47848868 0.10037275 −0.4321334 0.58255952 ZNF91 0.35273014 0.08161759 −0.2919523 0.5823168 KIAA1244 0.40223825 −0.0821994 −0.5820414 0.24385582 ZFC3H1 0.07459252 −0.2966751 −0.5819577 0.50165302 ARHGAP32 0.42885941 −0.2481662 −0.534148 0.58194702 MADD 0.20516328 −0.1842336 −0.1384043 0.58184949 NUMA1 0.35525434 −0.0665473 0.10531847 0.58179356 SAFB 0.18921843 −0.581786 −0.1703209 0.48735681 FRY 0.26128189 −0.2114183 0.23259285 0.58172025 ZBTB37 0.43702691 −0.1139302 −0.2354581 0.58165794 ABCC1 0.18408949 −0.4076036 −0.3436022 0.58159665 KIAA1462 −0.0369722 −0.2957843 −0.3958515 −0.581181 KLC1 0.12045277 0.19334898 0.07592528 0.580911 TNFAIP2 0.58082109 −0.1179663 −0.1069083 0.14039616 C11orf73 −0.1772893 0.18157432 −0.0987016 −0.5808104 MRPS7 −0.1540971 0.14995503 0.08995564 −0.5803809 GOLGA4 0.11484779 −0.0270357 0.0465447 0.58004838 VPS26A 0.21370065 −0.5207642 −0.5799409 −0.0120287 HAX1 −0.3162913 0.36316754 0.09355769 −0.5798084 AMOT 0.57969835 −0.0704498 −0.1051322 0.19246419 FN1 0.02926367 −0.0252838 −0.3393865 0.57945992 STOML2 −0.2016475 0.12723347 0.01645552 −0.5790051 PIN1 −0.0579407 0.24127051 0.04936464 −0.5780146 MTERFD1 −0.2388666 0.08309974 0.11054767 −0.5779766 RPS12 −0.1367366 0.21244554 0.09407296 −0.5778193 TXNDC17 0.01672647 0.14875685 0.17880615 −0.5774703 CYR61 0.01951561 −0.577428 −0.1953133 −0.4436776 UBAP2L 0.09107439 −0.1220571 −0.0303203 0.57729377 EIF4G3 0.07291953 0.01702326 −0.3976598 0.57666025 MTOR 0.2685828 −0.0683595 −0.1885263 0.5765338 SEPN1 0.13660324 −0.3024581 −0.5765135 0.465927 MYLK 0.27921701 −0.079535 −0.2195108 0.57649644 TMEM101 0.10155348 0.21010762 0.02120692 −0.5758062 BCL2L11 0.21834069 0.27879988 −0.575641 0.2806781 LUC7L3 −0.2715495 −0.0124251 0.57551263 0.46473987 ADH5 −0.0884563 0.088362 0.21255541 −0.575314 GCN1L1 0.29922506 −0.1576355 −0.1022072 0.57487343 FAU −0.0500859 0.31894667 0.07807538 −0.5745164 TLN1 0.29698121 −0.1488732 −0.1582954 0.5741382 PRKACA 0.13962128 0.09447358 −0.4928556 0.57372766 TIMP2 0.14055961 −0.2407639 −0.4450665 0.57318889 NSMCE1 −0.1532289 0.2044891 −0.0851212 −0.5730993 GALNS −0.0108121 −0.0157572 0.21085516 0.57305797 SERTAD1 −0.3327589 0.28644617 0.02202144 −0.5729135 NOTCH2NL 0.57286845 −0.5299901 −0.1938303 0.4941777 PSMC1 −0.0735354 −0.0133338 0.07395138 −0.5726789 EXOSC4 −0.1250863 0.26597249 0.18334276 −0.5721212 ZSCAN30 0.19336421 −0.002084 0.07963653 0.57199151 ADORA2B −0.128825 0.36304567 0.02468456 −0.5716074 SETD5 0.16133136 −0.2320933 −0.4820513 0.57159898 USP34 0.3031619 −0.1979102 −0.571417 0.39670192 MOV10 0.28747989 0.08448284 −0.2278989 0.5708904 SS18L2 −0.2598961 −0.2386609 0.24995563 −0.570576 NFIX 0.4487442 −0.4499578 −0.2783189 0.57057276 FRMD4A 0.06759762 −0.3506559 −0.3275229 0.57050485 AKIRIN2 0.0659957 −0.2158195 −0.5699803 0.04094788 HAUS1 −0.0803022 0.05839543 0.34763095 −0.5698397 NCOR1 0.18146096 −0.1365149 −0.3522181 0.56977585 RBBP6 0.07361438 0.0296485 −0.3997748 0.56957711 SSR4 −0.1612098 0.13625687 0.09518211 −0.5690535 ACTL6A −0.1166318 0.07240063 0.33716007 −0.5690428 SOD1 0.02576813 0.18437878 0.1240553 −0.5688333 NDUFB3 −0.0387811 0.29664904 0.31291233 −0.5680716 HERC2 0.56801277 −0.253225 −0.5294764 0.42908941 ATP5I −0.0562656 0.30105298 0.14927512 −0.5680001 FAM120B 0.02145747 −0.567595 −0.4581603 0.21523379 COX6A1 −0.0553017 0.18235164 −0.0115008 −0.5675486 PBX1 0.46050841 0.01243548 −0.2266404 −0.5675264 IGFBP6 −0.1252464 0.27561675 0.48165647 −0.5673845 AKAP9 0.21581127 −0.087094 −0.1098759 0.56734411 PLAU −0.5673287 −0.1208923 −0.209237 0.11024304 ANKFY1 0.28728414 −0.5670507 −0.489924 0.47855987 CPSF1 0.01858501 −0.105163 0.05693289 0.56636831 RNF181 0.05372649 0.18268907 −0.0024656 −0.5663306 TOMM7 −0.0883211 0.21282568 0.24889375 −0.5658542 LSM4 −0.0618379 0.25836229 0.06550459 −0.5656159 ATG5 −0.0195318 −0.0583603 0.01209598 −0.5650826 RPL5 −0.1386788 0.15779469 0.12552444 −0.565028 STARD3NL −0.0727079 0.12386452 0.20176155 −0.5649802 RBM14 −0.0684095 0.05433799 −0.3342708 0.56492846 AMPD2 −0.0410706 0.09101496 0.08424238 0.56492526 MAST2 0.17742984 −0.3716446 −0.1087907 0.56463898 FAM174A −0.1242805 −0.1416328 0.32441573 −0.5646133 RPS27L −0.1006892 0.20633141 0.14669635 −0.5645059 RHOG −0.0318366 0.00239613 0.0910649 0.56439051 PSMB4 −0.0038407 0.2127347 0.11048191 −0.5637491 SRRM1 0.08148667 −0.1316648 −0.5635081 0.56330303 NDUFB6 −0.1085849 0.30670713 0.13013016 −0.5634041 PPP3CA 0.21905449 −0.2709168 −0.5630928 0.17145656 IKZF5 −0.1056305 −0.4574443 −0.563053 0.48427223 MED24 0.14316795 0.03896264 0.05937926 0.5630384 ZNF142 0.18373347 −0.1949545 −0.5426388 0.56296111 PCDHGC3 −0.0964456 −0.1887165 −0.562752 0.40247203 TMEM214 0.24889452 −0.1851012 −0.0511774 0.56263044 TMEM14C −0.0545916 0.12380815 0.12934648 −0.5625395 RBM3 −0.0796274 0.04732422 0.13892706 −0.5619069 RHBDF2 −0.0435509 −0.3445649 −0.0452669 0.56181949 FRG1 −0.0290216 0.14024825 0.23229854 −0.5616458 COQ5 −0.1576225 0.05519564 0.00620944 −0.5605841 DCXR 0.01410179 0.23453438 −0.0696864 −0.5604387 PPP1R9B 0.10378623 −0.0465876 0.18280109 0.55994745 MRPL17 −0.1359594 0.16672228 0.06861519 −0.5589964 CTGF −0.2132757 −0.558971 −0.5088502 −0.3837502 RAB7A 0.02676518 −0.5588245 −0.4001748 0.28268406 SREBF1 −0.0373682 −0.0154967 −0.0132332 0.55850969 ATP5H −0.1837906 0.18001758 0.13515163 −0.5583839 TMEM208 0.03783463 0.22830451 0.47662752 −0.5582157 TIMMDC1 −0.1056647 0.23450937 0.12585896 −0.5579571 SLC50A1 0.09271278 0.22447123 −0.0383386 −0.5578085 CCDC57 0.03049013 −0.230491 0.04398965 0.55768048 ZNF462 0.51044446 −0.245407 −0.5574908 0.53701934 PBX3 0.06672902 −0.088653 −0.2325674 0.55697265 CELF2 0.46442181 0.05689647 −0.415574 0.55695957 C5orf28 0.01973129 −0.0719692 0.28731329 −0.556229 RPTOR 0.18549565 −0.0356531 −0.2628679 0.5561621 TET3 0.24804048 −0.2404849 −0.5559853 0.52136739 SELK 0.02544383 −0.0686865 0.17587077 −0.5559827 RAI1 0.3198781 −0.4547992 −0.5554582 0.15012235 PPA1 −0.0944888 −0.0017129 0.15944897 −0.5552173 MPG −0.1111622 0.22837236 −0.0366842 −0.5548056 PRDX5 −0.2081414 0.18055277 0.22167361 −0.5547389 TANC1 0.26441955 −0.3583628 −0.3847149 0.55448115 PRR14L 0.38125177 −0.1660961 −0.5153809 0.55447216 RNFT1 0.08160982 0.01388201 0.2251117 −0.5543453 ZFAND2A −0.089749 0.12900685 0.53579734 −0.5541725 HIST1H3B −0.174013 0.02844044 −0.0423323 0.5539376 PSMC5 0.05542158 −0.5536641 −0.3241225 0.03492764 TMEM218 −0.1024553 0.14234129 0.11674077 −0.5534551 FAM214A −0.1502468 −0.5534291 −0.5398987 0.2721808 ANKRD17 0.27227484 −0.165448 −0.3911186 0.55332563 SF1 0.02049894 −0.2413227 −0.1700993 0.55330612 CSNK2A2 0.0978229 −0.4124502 −0.5532296 0.30332224 APOL2 0.12380709 0.55295396 0.10435444 0.06757095 C9orf89 −0.0965402 0.37362362 0.10521518 −0.5529308 MARVELD1 0.0920998 −0.0396936 −0.1416973 0.55279349 UBE4B 0.07952726 0.00368896 −0.2495437 0.55278567 ADCY1 −0.4292595 −0.4413571 −0.2695221 0.55260388 PLXNB2 0.414472 −0.422416 −0.2276244 0.55258383 SPRY4 0.00105236 −0.1846097 0.55240283 0.45101859 TCEAL3 0.06046035 0.55213377 0.04806349 −0.1352728 AOX1 0.38574024 −0.0141461 −0.5520031 0.17468445 RELA 0.12621618 0.07646938 −0.0806561 0.55198731 TEFM 0.02192639 0.15355753 0.03058851 −0.551747 RPL27A −0.1062605 0.08405093 0.11159807 −0.5516193 CCDC12 0.22683203 0.55152437 0.26953684 −0.431155 IL27RA −0.5507006 −0.0117677 0.00344222 0.28382383 MAN2B2 0.22170079 −0.2233025 −0.0761453 0.55062616 TSPO −0.1622391 0.22312761 0.05241577 −0.5503484 TXN −0.0495886 0.19978955 0.15784693 −0.5501175 LAMTOR5 −0.0173054 0.0032075 0.33499889 −0.5500412 DYNLT1 −0.0804737 0.10839169 0.1390772 −0.5498241 CDK10 0.03159956 −0.0602099 0.54977639 −0.1762513 INTS3 0.01980387 −0.2066687 −0.1889085 0.54934334 PDS5B 0.14666468 −0.3991796 −0.5492778 0.13234049 B2M −0.1402403 0.09059853 0.25307709 −0.5492138 TAB2 0.09696458 −0.3469202 −0.5485589 0.41452399 SRPR 0.16851295 −0.5479903 −0.4459725 0.15583633 CEP170 0.12952091 −0.3773164 −0.183294 0.54792944 ZFYVE26 0.28225027 −0.0820584 −0.0754109 0.54768926 CLUH 0.14882095 −0.2047762 0.00691356 0.54767119 NCK1 0.01424151 0.03681804 0.18131492 −0.547378 ACACA 0.3182275 −0.4282022 −0.5470147 0.20322552 PLXNA3 0.06274598 −0.32651 −0.0916999 0.54688184 DCTN3 −0.0005519 0.1771386 0.20963098 −0.5467645 IPO9 0.10751791 −0.1619177 −0.2272642 0.54639746 ATXN10 −0.0656014 −0.3070797 −0.5461319 −0.4144326 RPSA −0.0528037 0.15902745 0.11785869 −0.5458575 CD82 −0.5453555 −0.0907558 −0.2513622 −0.0355855 HNRNPA2B1 −0.0847303 0.05491734 0.12889554 0.54534867 PCNXL3 0.23940964 −0.028154 −0.1407714 0.54526122 DLG5 0.22482403 −0.2941573 −0.1685403 0.54484573 NDUFB2 −0.0179394 0.22836765 0.11489402 −0.543856 SNX1 0.21318915 −0.54385 −0.3033339 0.00804938 ADAMTS1 −0.0442496 −0.2417127 0.09185611 0.54381249 CELSR1 0.3241773 −0.3784632 −0.5437458 0.46467174 RGP1 0.20668867 −0.1737492 −0.0446742 0.54358465 DDX6 0.27596183 −0.3474973 −0.5433117 0.29654869 ITGB1BP1 −0.070396 0.00284986 0.05871082 −0.5433111 NPTX1 0.54328732 −0.2173608 0.10778803 0.49260505 RUSC2 0.1782357 0.01625714 0.01430451 0.54313659 BOD1 −0.2378745 0.08792207 0.18434588 −0.5427684 ZFP36L2 0.53214408 −0.2837423 −0.2625826 0.54265881 GOLGB1 0.40524156 −0.1512733 −0.1536096 0.54226669 KIAA2026 0.3004757 −0.1614181 −0.2670171 0.54225858 TEAD1 0.15987569 −0.1167364 −0.3723834 0.54223578 STAT1 0.14527698 0.54217847 0.04550296 0.31588701 MED16 0.13214685 0.00767986 −0.3100873 0.54215918 NCKAP1 0.04849628 −0.0851515 −0.2493605 0.5415064 SNX11 −0.2828527 −0.122489 0.08286002 −0.5414856 ITPA −0.1581527 0.21845963 0.01916987 −0.5409746 SNRPF −0.0199678 0.24925543 0.33992809 −0.540838 RPL11 −0.0533179 0.1614374 0.1648822 −0.540793 IFNGR1 −0.1297576 0.00932483 0.35143084 −0.5404665 ZBTB8OS −0.0251358 0.06818483 0.10923555 −0.5402949 COPS3 −0.1355724 −0.0115668 0.07531204 −0.5401716 GTF3A 0.02215305 −0.0054405 0.08591066 −0.5400328 MYH10 0.33795632 −0.2004441 −0.0885091 0.53967835 FLRT2 0.01350983 −0.1837515 −0.2305458 0.53937713 C19orf10 −0.1224246 0.0216805 0.02129544 −0.5390284 FLNB 0.4647784 −0.1939721 −0.2126771 0.53848793 FOSL2 0.43563544 0.09849434 0.10220321 0.538395 MRPL23 −0.0115564 0.17133515 0.02101825 −0.5383191 PSMD10 0.03504185 0.20728358 0.17560179 −0.5381196 TMED3 −0.1536267 0.31326279 0.02922971 −0.537901 SLC5A6 −0.3003709 0.07750865 0.03959711 0.53768723 SH2B3 −0.1163054 −0.1450827 −0.2825038 0.53757918 HMGCS1 −0.3305917 −0.5370143 0.00832256 −0.2637056 MICAL2 0.11437893 −0.3012273 −0.5369197 0.5109278 MIB2 0.12512166 0.05208757 0.4430477 0.5367477 KIAA0922 0.00416956 −0.0041655 −0.1504559 0.53643396 GLIS3 0.00203391 −0.1055821 −0.5210895 0.53608693 OAZ1 −0.1245782 0.19175499 0.05039872 −0.53585 HTATIP2 0.02643847 0.07907669 0.29516068 −0.5354689 SYNJ1 0.13651481 −0.3894577 −0.5354501 0.52322086 DLG4 −0.0561056 −0.1397818 0.39153087 0.53478171 AMPD3 0.02660482 −0.0768976 −0.5346955 0.37069721 C1orf52 −0.1551285 0.17863385 0.17099136 −0.5339771 RPL27 −0.0950535 0.20910506 0.00249085 −0.5339142 CCDC90B −0.0203532 0.08365205 −0.0031126 −0.5335047 TAF12 −0.2037725 0.09053668 0.44392418 −0.5333095 PTMA −0.0263855 0.20299441 0.11506632 −0.5330454 DCP1A 0.0959493 0.12701547 −0.2292176 0.53301059 ZNF611 0.33941082 −0.338503 −0.3026404 0.53295984 PDCD5 −0.1816878 0.14341064 0.16735679 −0.5329234 SENP3 −0.049522 0.0405658 −0.0059901 −0.5326796 MYH9 0.31089449 −0.2766289 −0.0849269 0.53243457 UBB −0.1275473 0.34276553 0.25013562 −0.5322683 FOXJ2 0.0943295 −0.1707981 −0.532134 0.35974137 UBXN7 0.34426854 −0.4220562 −0.5320176 0.21032465 HIST1H2BC −0.2395357 0.09547506 0.10785155 −0.5318357 ZNFX1 0.28774959 0.23208658 −0.0871684 0.53148038 FNDC3B 0.13549415 −0.0913198 −0.3291899 0.53141716 FAM208B 0.23285088 −0.1084359 −0.1633975 0.53132134 HSPA5 −0.3371878 −0.5312859 −0.2252102 0.19921754 AFF4 0.31745645 −0.1968303 −0.530761 0.50764876 HIST1H2AE −0.2764649 0.10425154 −0.0134419 −0.5307397 FAM60A −0.1079917 −0.0895979 0.13742678 −0.5301617 42628 −0.1533024 0.05561799 0.18131649 −0.5299712 CLIC1 −0.1923872 0.16483548 0.13549438 −0.5295827 AGRN 0.27558339 −0.0579213 0.076167 0.52925189 APTX 0.04982703 0.09702217 0.18911084 −0.5292267 PSMB3 −0.1170493 0.22811528 0.02866022 −0.5289281 SASH1 0.23063043 −0.1508981 −0.3022163 0.52843822 CLTA −0.0160922 0.19449866 0.0284277 −0.5283923 RHEB −0.0854633 0.11298084 0.14423935 −0.5280287 DNAJA2 −0.0290591 0.11076994 0.22349002 −0.5279776 UBA2 −0.121009 −0.0177761 0.07974037 −0.5278594 VPS13B 0.31899421 −0.2888357 −0.5278486 0.39657989 DPAGT1 −0.0092699 −0.0179682 0.00097294 0.52759332 NCOA1 0.11922704 −0.0770116 −0.3367521 0.52759176 COA6 −0.2018072 0.01181063 0.20666232 −0.5273021 UTRN 0.5272641 −0.1507467 −0.3697148 0.41744473 NMB −0.0803696 0.52653001 0.25605111 −0.386272 GSKIP −0.0953593 0.06274327 0.15604186 −0.5265042 CBX5 0.40516196 −0.3362878 −0.5255397 0.52631335 B4GALT6 0.14903867 −0.2551047 −0.5258619 −0.2885695 PIEZO1 0.26726074 −0.0839819 0.10616602 0.5257401 TACC2 0.07785822 0.05357652 −0.3045174 0.52568547 USP2 0.18524173 −0.2238737 −0.1428463 0.5256606 NFU1 0.02382332 −0.1171561 0.09135458 −0.5256517 MAPK1IP1L 0.08474335 −0.049168 −0.439918 0.5255741 PUM2 0.14354758 −0.525253 −0.5039825 0.30639196 BCL9L 0.43148049 −0.5247745 −0.382059 0.2162332 SSR1 −0.1341022 −0.0152326 −0.5245806 0.1665891 ITPK1 −0.1475098 0.02564897 −0.2163489 0.52443003 MAPKBP1 0.35639774 −0.1954318 −0.09164 0.52421017 ZNF318 0.16221073 −0.1305823 −0.4172037 0.52397477 ETHE1 −0.1236209 0.12825111 −0.0149539 −0.5239603 ZCCHC10 −0.0469071 0.17484015 0.20658526 −0.5235749 SPRED2 0.29759305 −0.2433991 −0.4984676 0.52357348 PRKCA 0.47320811 −0.3568228 −0.5161944 0.52322305 CHD7 0.04625625 −0.5171732 −0.3726806 0.52319348 TFAP2A 0.07020193 −0.0046544 −0.5081897 0.52290499 MEA1 −0.1140631 0.25307496 0.13728377 −0.5228735 RPL8 −0.0691117 0.19718839 0.11204859 −0.5228686 ATP5G1 −0.0987907 0.25777759 0.05680114 −0.5228324 RALGAPB 0.16790084 −0.1272312 −0.2349644 0.52243123 ATP6V1F −0.1494279 0.23550716 0.02011351 −0.5224178 SMIM7 0.03026485 0.16906032 0.10619775 −0.5222803 C1orf50 −0.0074135 −0.1316025 −0.0585286 −0.5217887 ATXN1L 0.20851962 −0.0546624 −0.0138853 0.52166478 TAOK3 0.0538397 −0.2896611 −0.3525882 0.52161088 HIVEP2 0.50606996 −0.2700093 −0.3116946 0.52112415 STS 0.16837591 0.0330668 −0.5211023 0.10023032 WDR26 0.21678475 −0.2614728 −0.5205466 0.25525346 TOP2A 0.23197873 −0.0157788 −0.0004755 0.52031806 CCDC6 0.00012011 0.02476587 −0.5199046 0.34146741 VPS13D 0.51979295 −0.1525629 −0.3394081 0.44907785 RNF38 0.10221754 −0.0880927 −0.4384741 0.51959276 KDM2A 0.20039343 −0.1247406 −0.1651819 0.5194527 ASNS −0.5193598 0.1240141 −0.0700706 −0.1460477 CKAP5 0.21754962 0.01758074 −0.0924651 0.51925607 VPS29 0.03956266 0.01277438 0.12846054 −0.5191764 HNRNPA0 0.16706893 −0.5189423 0.01159142 0.21449568 NUDT14 −0.0876665 −0.3162849 −0.2012516 −0.5185342 SLC35F6 0.05645232 −0.1211496 −0.3064036 0.51820084 CDK5RAP3 −0.1167549 0.32194979 0.51819039 0.2764768 RGS10 −0.3211278 −0.0010253 0.04414248 −0.5181831 CNIH1 0.02619286 −0.0627346 −0.0793689 −0.517949 NAE1 −0.0675087 0.01645091 0.19791498 −0.5177712 MPHOSPH8 0.03397299 0.04108847 −0.1430365 0.51749399 KHDRBS1 0.27910105 −0.5172959 −0.5092018 0.05568034 TRIM41 −0.1116196 0.35823232 0.2769105 0.51727731 UBE2B 0.11653441 −0.5172532 −0.2155054 −0.2752584 RAP1A 0.13294147 −0.516972 −0.2720791 −0.232872 WASF2 0.34014255 −0.3643959 −0.4821383 0.51616254 RBM15 0.22202537 −0.055309 −0.0579706 0.51605167 UBQLN2 −0.1277609 −0.3052531 −0.5159802 0.47426771 EIF4G1 0.1182776 −0.0449694 −0.0198472 0.5157993 NDST1 0.24911668 −0.0661302 −0.1304274 0.51573738 PRDM10 0.1337423 −0.2275514 −0.0212149 0.51568876 TNRC6A 0.19319192 −0.2209476 −0.0754911 0.51556923 NDUFB8 −0.0163846 −0.0082133 0.17564266 −0.5154261 ISOC2 −0.0271062 0.3686245 0.05562535 −0.5150801 HOOK3 0.256545 −0.3867896 −0.5149002 0.26530616 PLEKHJ1 −0.2399147 0.24455101 0.2686366 −0.5141846 LGALS1 −0.1069833 0.29501308 0.34698272 −0.5140236 VPS25 −0.1516772 0.17746878 −0.035588 −0.513589 ATF7IP 0.23155413 −0.3138314 −0.4273379 0.51355202 CARD9 −0.2608557 0.24247539 0.22937184 0.51328723 GOLGA3 0.30791259 −0.0979988 −0.0860339 0.51305286 SYNJ2 0.16974842 −0.1488112 −0.0425671 0.51292699 ITGB8 0.26196209 0.27879816 −0.5128835 0.50419115 PPARD −0.1151066 −0.1069367 −0.239489 0.51276537 H6PD 0.33567325 −0.2253079 −0.2978887 0.51213646 CBS −0.5120212 0.14999835 0.14907323 0.20563307 TATDN1 −0.1475095 −0.0219852 0.17354358 −0.5116292 POMK 0.04008045 −0.094102 −0.2373362 0.51160621 TNKS1BP1 0.35298111 0.00989539 0.19019798 0.51156449 ATP2B4 0.47159024 −0.2346006 −0.5115096 0.36158347 DHX38 0.20496812 0.10325314 0.08395173 0.51141946 TAOK1 0.38993145 −0.1713866 −0.2876863 0.51130902 PSMD13 −0.097676 0.15388899 0.10577048 −0.5112565 DOPEY2 0.51019407 −0.0884928 −0.308042 0.3938517 IGF2R 0.47067548 −0.4318273 −0.3895396 0.5095359 HIVEP1 0.22127371 −0.0720493 −0.5089846 0.40328838 TIAM2 0.50879968 −0.0060125 −0.3983448 0.28149008 DDX39B −0.5087881 −0.2655738 0.27205764 0.34306313 TTYH3 0.46459361 −0.2733159 −0.234031 0.50845309 TXNDC9 0.03090648 0.16579991 0.21894476 −0.5082878 KIF13A 0.29781575 −0.0189662 −0.0808723 0.50824021 GLRX3 −0.069425 0.1251562 0.05036684 −0.5078272 TIMM17B −0.1101356 0.2747208 −0.0117336 −0.5077371 ALKBH2 −0.4539901 0.24612219 0.50765447 −0.1551417 SCAND1 −0.0432603 0.2866841 −0.0676189 −0.5071335 ELP5 −0.02016 0.05505045 0.00174334 −0.5069586 DOPEY1 0.3066845 −0.0577204 −0.0144031 0.50691517 TCOF1 0.14378755 −0.0077061 −0.0176247 0.50680879 MGST3 −0.0970302 0.17860739 0.13488892 −0.5066877 NFRKB −0.0193744 0.10390296 0.03949668 0.50644244 PNN −0.004587 0.07446417 0.39988232 0.50634605 CDC123 −0.106382 0.07694548 0.14202872 −0.5060748 PPP2R5E 0.07359214 −0.2740628 −0.5056397 0.12025767 TCERG1 −0.0593964 0.00679815 0.00402833 0.50559988 SPHK1 −0.5048876 0.1666443 0.50147085 −0.1904178 TBC1D16 0.22961629 −0.0954713 0.0054563 0.50466407 RPL29 −0.0382206 0.24659113 0.03319595 −0.5046262 ATP7A 0.33109761 −0.0442711 −0.1145455 0.50462524 TNKS 0.14055398 −0.1143356 −0.3073172 0.50439103 PRTG −0.0127114 0.00552363 −0.5040723 0.35503648 GFOD1 0.06292123 −0.0310921 0.03732134 0.50400566 SMC4 0.10694852 −0.2129709 −0.1281865 0.50369359 MYCBP2 0.50364064 −0.1013739 −0.4058507 0.48207889 ACADVL −0.1957301 0.12070285 0.50350563 0.14778155 HMGA1 0.13590961 0.01151469 −0.1122424 0.50338802 HNRNPM 0.14995869 −0.1989986 −0.1602786 0.50328508 C1orf54 0.09571617 0.1917904 0.16669633 −0.5026295 NDUFS5 −0.0432345 0.19605896 0.0790887 −0.5026206 ADSL −0.1888454 0.14906963 0.12194149 −0.5022232 AP3D1 0.11118791 −0.0357219 0.04693049 0.50209159 SETD1A 0.2709323 −0.5015214 −0.4543843 0.31215405 TNFAIP3 0.18669904 −0.5015093 −0.2886948 0.39744213 RYBP 0.07093389 −0.2771175 −0.500935 0.12758249 RPLP1 −0.1198657 0.16404093 −0.0647548 −0.5009318 NDUFC1 −0.1030795 0.0440726 0.09811742 −0.5008456 TEP1 0.10532 −0.2414393 0.08085992 0.5005537 WDR7 0.34077546 −0.0437672 −0.2479611 0.50048656 AGAP1 0.37761605 −0.0898255 −0.0848244 0.50045323 RFK 0.00601232 0.00793012 0.05656493 −0.500388 PCNT 0.46283256 −0.2965203 −0.133546 0.50035115 MOB3A −0.0307228 −0.2325328 −0.1942487 0.50034547

REFERENCES Example 2

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Embodiments

Embodiment 1: A method of treating a Zika viral infection, said method comprising administering to a subject in need thereof an effective amount of a compound as set forth in any of FIG. 1A, 1B, 2, 3, 6, 8, or 9.

Embodiment 2: The method of embodiment 1, wherein said compound is Ganciclovir, Procaine hydrochloride. Zidovudine. Acyclovir. Drostanolone Propionate, Dapivirine (TMC120), Tilorone hydrochloride, or Docosanol.

Embodiment 3: A method of treating a Zika viral infection, said method comprising administering to a subject in need thereof an effective amount of an inhibitor of NS5 polymerase.

Embodiment 4: The method of embodiment 3, wherein said inhibitor of NS5 polymerase is beclabuvir, dasabuvir, deleobuvir, filibuvir, radalbuvir, setrobuvir, or sofosbuvir.

Embodiment 5: The method of embodiment 3 or 4, wherein said inhibitor of NS5 polymerase is sofosbuvir.

Embodiment 6: A method of treating a Zika viral infection, said method comprising administering to a subject in need thereof an effective amount of an HIV protease inhibitor.

Embodiment 7: The method of embodiment 6, wherein said HIV protease inhibitor is nelfinavir.

Embodiment 8: A method of treating a Zika viral infection, said method comprising administering to a subject in need thereof an effective amount of a calcium channel blocker.

Embodiment 9: The method of embodiment 8, wherein said calcium channel blocker is manidipine, cilnidipine, or benidipine.

Embodiment 10: A method of treating a Zika viral infection, said method comprising administering to a subject in need thereof an effective amount of a combination therapeutic composition comprising an NS5 polymerase inhibitor and a HIV protease inhibitor, according to any one of embodiments 1 to 7.

Embodiment 11: The method of any one of embodiments 1 to 7, or 10, wherein said combination therapeutic composition comprises Suramin, Ganciclovir, Procaine hydrochloride, Zidovudine, Acyclovir, Drostanolone Propionate, Dapivirine (TMC120), Tilorone hydrochloride, Docosanol, clomiphene, amphotericin B, toremifene, mycophenolic acid, fluoxetine, niclosamide, or polyhydroxyalkanoate (PHA).

Further Embodiments

Embodiment 1. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an NS5 polymerase inhibitor.

Embodiment 2. The method of embodiment 1, wherein said NS5 polymerase inhibitor is beclabuvir, dasabuvir, deleobuvir, filibuvir, radalbuvir, setrobuvir, or sofosbuvir.

Embodiment 3. The method of embodiment 1 or 2, wherein said NS5 polymerase inhibitor is sofosbuvir.

Embodiment 4. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an HIV protease inhibitor.

Embodiment 5. The method of embodiment 4, wherein said HIV protease inhibitor is amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.

Embodiment 6. The method of embodiment 4 or 5, wherein said HIV protease inhibitor is nelfinavir.

Embodiment 7. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject a combined effective amount of an NS5 polymerase inhibitor and an HIV protease inhibitor, according to any one of embodiments 1 to 6.

Embodiment 8. The method of any one of embodiments 1 to 7, wherein said NS5 polymerase inhibitor is beclabuvir, dasabuvir, deleobuvir, filibuvir, radalbuvir, setrobuvir, or sofosbuvir.

Embodiment 9. The method of any one of embodiments 1 to 7, wherein said HIV protease inhibitor is amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.

Embodiment 10. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a protein or a gene encoding the protein, wherein the protein is a ZIKV non-structural (NS) protein, ZIKV protease, or ZIKV RNA polymerase.

Embodiment 11. The method of embodiment 10, wherein the ZIKV NS protein is NS5.

Embodiment 12. The method of embodiment 10 or 11, wherein the ZIKV NS protein is NS2B-NS3.

Embodiment 13. The method of any one of embodiments 10 to 12, wherein the ZIKV protein is NS5 RNA polymerase.

Embodiment 14. The method of any one of embodiments 10 to 13, wherein the ZIKV protein is NS2B-NS3 protease.

Embodiment 15. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an inhibitor, wherein the inhibitor is suramin, ganciclovir, procaine hydrochloride, zidovudine, acyclovir, drostanolone propionate, dapivirine, tilorone hydrochloride, docosanol, clomiphene, amphotericin B, toremiphine, mycophenolic acid, fluoxetine, niclosamide, polyhydroxyalkanoate, or a combination thereof, according to any one of embodiments 1 to 14. 

What is claimed is:
 1. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an NS5 polymerase inhibitor.
 2. The method according to claim 1, wherein said NS5 polymerase inhibitor is beclabuvir, dasabuvir, deleobuvir, filibuvir, radalbuvir, setrobuvir, or sofosbuvir.
 3. The method according to claim 2, wherein said NS5 polymerase inhibitor is sofosbuvir.
 4. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an HIV protease inhibitor.
 5. The method according to claim 4, wherein said HIV protease inhibitor is amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.
 6. The method according to claim 5, wherein said HIV protease inhibitor is nelfinavir.
 7. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject a combined effective amount of an NS5 polymerase inhibitor and an HIV protease inhibitor.
 8. The method according to claim 7, wherein said NS5 polymerase inhibitor is beclabuvir, dasabuvir, deleobuvir, filibuvir, radalbuvir, setrobuvir, or sofosbuvir.
 9. The method according to claim 7, wherein said HIV protease inhibitor is amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, paritaprevir, simeprevir, or telaprevir.
 10. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a protein or a gene encoding the protein, wherein the protein is a ZIKV non-structural (NS) protein, ZIKV protease, or ZIKV RNA polymerase.
 11. The method of claim 10, wherein the ZIKV NS protein is NS5.
 12. The method of claim 10, wherein the ZIKV NS protein is NS2B-NS3.
 13. The method of claim 10, wherein the ZIKV protein is NS5 RNA polymerase.
 14. The method of claim 10, wherein the ZIKV protein is NS2B-NS3 protease.
 15. A method of treating a Zika viral infection in a subject in need thereof, said method comprising administering to said subject an effective amount of an inhibitor, wherein the inhibitor is suramin, ganciclovir, procaine hydrochloride, zidovudine, acyclovir, drostanolone propionate, dapivirine, tilorone hydrochloride, docosanol, clomiphene, amphotericin B, toremiphine, mycophenolic acid, fluoxetine, niclosamide, polyhydroxyalkanoate, or a combination thereof. 